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1.
J Hand Microsurg ; 16(1): 100012, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38854369

ABSTRACT

Background: Utilization of magnetic resonance imaging (MRI) and computed tomography (CT) increases annually, raising concerns about overuse. Imaging appropriateness guidelines have the potential to standardize decisions regarding imaging based on best evidence, which might reduce unhelpful or potentially misleading imaging. We studied expert use of advanced imaging for musculoskeletal illness compared to published appropriateness recommendations. Methods: First, 15 imaging guidelines with recommendations for advanced imaging of the upper extremity were collated. Next, members of the Science of Variation Group (SOVG) were invited to participate in a survey of 11 patient scenarios of common upper extremity illnesses and asked whether they would recommend MRI or CT. Guideline recommendations for imaging were compared with surgeon recommendations using Fisher's exact tests. We used Fleiss' kappa to measure the interobserver agreement among surgeons. Results: For the 11 scenarios, most imaging appropriateness guidelines suggested that MRI or CT is useful, while most surgeons (n = 108) felt it was not. There was no correlation between surgeons and guidelines recommendations for imaging (ρ = 0.28; p = 0.40). There was slight agreement among surgeons regarding imaging recommendations (kappa: 0.17; 95% confidence interval: 0.023-0.32). Conclusion: The available imaging appropriateness guidelines appear to be too permissive and therefore seem to have limited clinical utility for upper extremity surgeons. The notable surgeon-to-surgeon variation (unreliability) in recommendations for advanced imaging in this and other studies suggests a role for strategies to ensure that patient decisions about imaging are consistent with their values (what matters most to them) and not unduly influenced by patient misconceptions about imaging or by surgeon beliefs and habits. Level Of Evidence: II, diagnostic.

2.
J Occup Environ Med ; 2024 May 10.
Article in English | MEDLINE | ID: mdl-38729188

ABSTRACT

OBJECTIVE: We selected statements in the Official Disability Guidelines (ODG) that had the potential to reinforce misconceptions regarding symptoms from rotator cuff tendinopathy (RCT). These statements were revised and presented with the original statement to specialists. METHODS: Twelve statements regarding RCT were identified as deviating from principles based on ethics, values, and the evidence regarding both pathophysiology and human illness behavior. One hundred fifteen upper extremity surgeons reviewed both original and revised versions of the statements and indicated their preference. RESULTS: We found that upper extremity surgeons preferred 3 revised statements, 4 ODG statements, and 5 were rated as neutral between the 2 statements. CONCLUSION: Statements revised for evidence, ethics, and healthy mindset were not preferred by specialists, which may indicate limited awareness about how negative thoughts and distressing symptoms impact human illness.

3.
Proc (Bayl Univ Med Cent) ; 37(1): 101-103, 2024.
Article in English | MEDLINE | ID: mdl-38173992

ABSTRACT

Background: Medical students who are exposed to value-based care early in their education may be more likely to practice it. Our study aimed to understand medical students' knowledge of and ability to implement the principles of high-value care in clinical settings. Additionally, we assessed students' confidence in using high-value care practices to both influence care decisions and educate patients. Methods: We surveyed third-year medical students at Texas A&M School of Medicine during their clerkship rotations using a 7-question Likert-scale survey. Students were asked to evaluate their confidence in performing cost-conscious high-value care behaviors. Results: Of the 114 students offered the survey, 34 (30%) completed it fully. The greatest variance in response occurred in students' attitudes toward their role in controlling healthcare costs. Half of respondents agreed or strongly agreed that they played a part in cost control as medical students, with 35% somewhat or strongly disagreeing. A majority of students felt confident initiating a conversation about costs with patients, while 21% somewhat or strongly disagreed that they were confident. Conclusion: Overall, our results reveal that the main area lacking in students' education in value-based care is instilling the belief that they, as medical students, have a role to play in controlling healthcare costs.

4.
J Foot Ankle Surg ; 63(2): 226-232, 2024.
Article in English | MEDLINE | ID: mdl-37984694

ABSTRACT

Hallux valgus (HV) is a common condition in which the first ray is deformed, leading to pain and altered joint mechanics. A variety of radiographic measurements are used to evaluate HV. Little is known about measurements used in the assessment of HV on lateral radiographs compared to anteroposterior (AP) radiographs. The primary aim of this study was to correlate lateral measurements with AP measurements pre and postoperatively. The secondary aim was to correlate lateral measurements with patient-reported outcome measures (PROMs) pre and postoperatively. One hundred eighty-three patients were initially enrolled in the study. Two fellowship-trained musculoskeletal radiologists independently performed all measurements. On AP radiographs, hallux valgus angle (HVA) and intermetatarsal angle (IMA) were measured. On lateral radiographs, sagittal IMA, Meary's angle, and sagittal first ray length were measured. Measurements were recorded at baseline and 6, 12, and 24 months postoperatively. Intraclass correlation coefficients (ICCs) were used for inter-reader analysis. ICCs were moderate to very strong among readers. There were significant but weak correlations between lateral measurements and AP measurements. For at least 1 timepoint, IMA correlated with sagittal IMA, sagittal first ray length, and Meary's angle. HVA only correlated with sagittal first ray length. These correlations were all weak in magnitude. There were a few significant but weak correlations between the measurements in the study and PROMs. This study showed that sagittal IMA, sagittal first ray length, and Meary's angle are not predictive of AP measurements or patient outcomes and are not useful in preoperative assessment of HV.


Subject(s)
Bunion , Hallux Valgus , Metatarsal Bones , Humans , Hallux Valgus/diagnostic imaging , Hallux Valgus/surgery , Prospective Studies , Foot , Patient Reported Outcome Measures , Retrospective Studies , Metatarsal Bones/surgery
5.
Skeletal Radiol ; 52(12): 2419-2425, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37199757

ABSTRACT

OBJECTIVE: To determine inter-reader reliability (IRR) of hallux valgus (HV) related parameters, i.e. intermetatarsal angle (IMA), hallux valgus angle (HVA), lateral round sign of the first metatarsal, tibial sesamoid position (TSP), metatarsus adductus angle (MAA), transverse osseous foot width, 1st MT length, MTP osteoarthritis (OA), and distal metatarsal articular angle (DMAA). These were correlated with patient-reported outcome measures (PROMs). MATERIALS AND METHODS: A prospective single-arm Level 3 multicenter clinical trial in which standardized radiographs and PROMs were collected at the time of the initial patient visit for pre-operative assessment. Two musculoskeletal radiologists performed measurements blinded to each other's reads and clinical information. Intraclass coefficient and kappa were obtained for inter-reader analysis. A partial spearman rank order was used to correlate the measurements with PROMs. RESULTS: The final cohort size of 183 patients had mean age of 40.77 years, mean body mass index was 26.11 kg/m2, with 91.2% females and 8.7% males. There was excellent IRR for HVA (0.96, CI: [0.94,0.97]), IMA (0.92, CI: [0.89,0.94]), transverse osseous foot width (0.99, CI: [0.98,1.00]), and DMAA (0.80, CI: [0.74, 0.85]), good agreement for TSP (0.73, CI:[0.67,0.79]) and MAA (0.67, CI: [0.16, 0.84]), fair agreement for MTP OA (0.48, CI: [0.36,0.59]), and poor agreement for lateral round sign (0.32, CI: [0.11, 0.52]. The negative correlation of increasing transverse osseous foot width with worsening PROMIS physical but better MOxFQ and VAS scores is likely spurious. CONCLUSION: Good to excellent inter-reader reliability was observed for the most often used measurements for HV assessment without major trends in their correlations with PROMs. Lateral round sign is not a reliable finding in HV deformity.


Subject(s)
Hallux Valgus , Metatarsal Bones , Osteoarthritis , Adult , Female , Humans , Male , Hallux Valgus/diagnostic imaging , Patient Reported Outcome Measures , Prospective Studies , Reproducibility of Results , Retrospective Studies , Treatment Outcome , Weight-Bearing
6.
Skeletal Radiol ; 52(11): 2283-2296, 2023 Nov.
Article in English | MEDLINE | ID: mdl-36287234

ABSTRACT

Glenohumeral osteoarthritis (GHOA) is a widely prevalent disease with increasing frequency due to population aging. Both clinical manifestations and radiography play key roles in the initial diagnosis, staging, and management decisions. Radiographic disease progression evaluation is performed using validated staging systems, such as Kellgren and Lawrence, Samilson, and Hamada. For young patients with mild to moderate GHOA and failed conservative treatment, arthroscopic preservation surgery (APS) is usually considered. Older patients and those with severe GHOA benefit from different types of arthroplasties. Preoperative magnetic resonance imaging (MRI) is essential for APS surgical planning, as it maps repairable labral, cartilage, and rotator cuff lesions. For arthroplasty planning, the status of glenoid cartilage and intactness of rotator cuff as well as glenoid morphology represent key factors guiding the decision regarding the most suitable hardware design, whether resurfacing, partial, total, or reverse joint replacement. Pre-surgical MRI or alternatively computed tomography arthrogram is employed to evaluate the cartilage and rotator cuff. Finally, three-dimensional computed tomography (3D CT) is indicated to optimally assess the glenoid morphology (to determine Walch classification, version, inclination, and bone loss) and analyze the necessity for glenoid osteotomy or graft augmentation to correct the glenoid structural abnormalities for future success and longevity of the shoulder implants or chosen constructs. Understanding the purpose of each imaging and treatment modality allows more efficient image interpretation. This article reviews the above concepts and details what a surgeon needs from a radiologist and could benefit from accurate reporting of preoperative imaging studies.


Subject(s)
Arthroplasty, Replacement , Osteoarthritis , Shoulder Joint , Surgeons , Humans , Shoulder Joint/diagnostic imaging , Shoulder Joint/surgery , Shoulder Joint/pathology , Arthroplasty, Replacement/methods , Osteoarthritis/diagnostic imaging , Osteoarthritis/surgery , Radiologists , Retrospective Studies
7.
Iowa Orthop J ; 42(1): 283-286, 2022 06.
Article in English | MEDLINE | ID: mdl-35821942

ABSTRACT

Background: Physicians with a large number of reviews and a high rating may be employing reputation management strategies. Specialists may be more likely than non-specialists to employ such strategies. This should be apparent in a study of online physician reviews on physician rating websites (PRW). Methods: Using one physician rating website, we gathered orthopedic surgeon and family physician reviews. We measured Spearman correlations between the number of reviews and average numerical rating and used chi-squared to test threshold relationships. Results: There were very small negative Spear-man correlations between the number of online reviews and the average numerical rating for orthopedic surgeons (p= -0.097, p-value=<0.001) family medicine physicians (p= -0.170, p-value=<0.001; Figure 2). Physicians with more than 100 reviews had a greater average numerical rating than physicians with fewer than 50 reviews. Orthopedic surgeons are more likely than family medicine physicians to have a large number of reviews and average numerical rating greater than 3. Conclusion: The small fraction of physician with a high number of reviews may be utilizing reputation management strategies, and this seems relatively specific to specialists rather than non-specialists. Level of Evidence: III.


Subject(s)
Orthopedic Surgeons , Physicians , Humans , Patient Satisfaction
8.
J Occup Environ Med ; 64(7): e424-e430, 2022 07 01.
Article in English | MEDLINE | ID: mdl-35672919

ABSTRACT

OBJECTIVE: Workers' compensation guidelines may reinforce unhelpful thoughts regarding symptoms that are known to increase symptom intensity and magnitude of incapability. METHODS: One guideline commonly used (the Official Disability Guidelines) was reviewed regarding carpal tunnel syndrome. For 15 statements, we created an alternative statement based on a set of consensus principles for health, value, and quality in care. One hundred eight upper extremity surgeons of the Science of Variation Group reviewed both versions of the statements to indicate their preference. RESULTS: Surgeons preferred seven revised statements and five guideline statements and were neutral on three statements. Favored revisions related to more accurate discernment of symptoms that are clearly related to idiopathic median neuropathy and representative of severity of pathology. CONCLUSIONS: There may be important mental health considerations for care under a work claim, such as unhelpful thoughts or distress regarding symptoms, which are not adequately considered by the Official Disability Guidelines.


Subject(s)
Carpal Tunnel Syndrome , Disabled Persons , Carpal Tunnel Syndrome/surgery , Carpal Tunnel Syndrome/therapy , Communication , Humans , Workers' Compensation
9.
J Addict Dis ; 40(4): 552-558, 2022.
Article in English | MEDLINE | ID: mdl-35274598

ABSTRACT

Reddit is an online social media website where users set up individual discussion forums (subreddits) on various topics. To gauge public perceptions of the opioid epidemic in the United States we analyzed discussions on the subreddits r/ChronicPain, r/Opiates, r/Politics, r/Health, r/News, and r/Science that were identified with the search terms "opioid", "opioid crisis", and "opioid epidemic". We identified categories in each subreddit and used IBM Watson Natural Language Understanding to analyze emotional tones and themes in comments from individual discussion posts. There were similar categories across subreddits including Health and Fitness, Addiction, Drugs, Disease, and Chronic Pain. Some categories and concepts were subreddit-specific such as the category "Law, Government, Politics" in r/News and the concept "analgesic" in r/Health. Across these subreddits and categories, there was an overall negative sentiment, with little difference in emotional tones. Themes were also similar across subreddits and categories and were limited to specific drugs: opioid, heroin, and morphine. Tone and theme analysis of public perceptions of the opioid epidemic on Reddit documented the negative sentiments associated with specific opioids among people from many different perspectives.


Subject(s)
Epidemics , Social Media , Analgesics, Opioid/adverse effects , Heroin , Humans , United States/epidemiology
10.
Clin Orthop Relat Res ; 480(8): 1576-1581, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35023866

ABSTRACT

BACKGROUND: Carpal tunnel release can stop the progression of idiopathic median neuropathy at the wrist (carpal tunnel syndrome). Intermittent symptoms tend to resolve after surgery, but loss of sensibility can be permanent. Both pathophysiology (severe neuropathy) and mental health (symptoms of despair or worry) contribute to problematic recovery after carpal tunnel release, but their relative associations are unclear. QUESTION/PURPOSE: Is problematic initial recovery after carpal tunnel release associated with psychologic distress rather than with disease severity? METHODS: We retrospectively studied 156 patients who underwent in-office carpal tunnel release between November 2017 and February 2020, and we recorded their symptoms of anxiety (Generalized Anxiety Disorder-7 [GAD]) and depression (Patient Health Questionnaire), signs of severe median neuropathy (loss of sensibility, thenar muscle atrophy, and palmar abduction weakness), and problematic recovery. The initial recovery (first 2 weeks) was categorized as problematic if the patient was upset about persistent numbness, experienced unsettling postoperative pain, developed hand stiffness, or experienced wound issues-all of which are routinely recorded in the medical record by the treating surgeon along with signs of severe median neuropathy. Twenty-four percent (38 of 156) of patients had a problematic initial recovery characterized by distress regarding persistent numbness (16% [25 of 156]), unsettling pain (8% [12 of 156]), hand stiffness (5% [8 of 156]), or wound issues (1% [2 of 156]); 6% (9 of 156) of patients had more than one issue. Associations between problematic initial recovery and age, gender, symptoms of anxiety and depression, disease severity, specific exam findings, and insurance were evaluated using t-tests, Mann-Whitney tests, and chi-square tests, with the plan to perform logistic regression if at least two variables had an association with p < 0.10. RESULTS: The only factor associated with problematic initial recovery was greater symptoms of anxiety (median GAD score 1.5 [interquartile range 0 to 7.8] for problematic initial recovery compared with a median score of 0 [IQR 0 to 2] for nonproblematic recovery; p = 0.04), so we did not perform a logistic regression. Physical examination findings consistent with severe median neuropathy were not associated with problematic initial recovery. CONCLUSION: The finding that problematic initial recovery after carpal tunnel release was related to symptoms of anxiety and not to the severity of median neuropathy highlights the need to study the ability of efforts to ameliorate anxiety symptoms before carpal tunnel release as an effective intervention to reduce unplanned visits and additional tests, therapy, and repeat surgery, while improving patient-reported outcomes and experience. LEVEL OF EVIDENCE: Level III, therapeutic study.


Subject(s)
Carpal Tunnel Syndrome , Median Neuropathy , Anxiety/diagnosis , Anxiety/etiology , Carpal Tunnel Syndrome/diagnosis , Carpal Tunnel Syndrome/surgery , Humans , Hypesthesia/complications , Median Neuropathy/complications , Retrospective Studies
11.
CPT Pharmacometrics Syst Pharmacol ; 11(2): 240-251, 2022 02.
Article in English | MEDLINE | ID: mdl-34877817

ABSTRACT

Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The common ΔF508-CFTR mutation results in protein misfolding and proteasomal degradation. If ΔF508-CFTR trafficks to the cell surface, its anion channel function may be partially restored. Several in vitro strategies can partially correct ΔF508-CFTR trafficking and function, including low-temperature, small molecules, overexpression of miR-138, or knockdown of SIN3A. The challenge remains to translate such interventions into therapies and to understand their mechanisms. One approach for connecting such interventions to small molecule therapies that has previously succeeded for CF and other diseases is via mRNA expression profiling and iterative searches of small molecules with similar expression signatures. Here, we query the Library of Integrated Network-based Cellular Signatures using transcriptomic signatures from previously generated CF expression data, including RNAi- and low temperature-based rescue signatures. This LINCS in silico screen prioritized 135 small molecules that mimicked our rescue interventions based on their genomewide transcriptional perturbations. Functional screens of these small molecules identified eight compounds that partially restored ΔF508-CFTR function, as assessed by cAMP-activated chloride conductance. Of these, XL147 rescued ΔF508-CFTR function in primary CF airway epithelia, while also showing cooperativity when administered with C18. Improved CF corrector therapies are needed and this integrative drug prioritization approach offers a novel method to both identify small molecules that may rescue ΔF508-CFTR function and identify gene networks underlying such rescue.


Subject(s)
Cystic Fibrosis , MicroRNAs , Cell Line , Cystic Fibrosis/drug therapy , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Drug Discovery , Humans , MicroRNAs/genetics , Mutation
12.
CPT Pharmacometrics Syst Pharmacol ; 10(5): 500-510, 2021 05.
Article in English | MEDLINE | ID: mdl-33934548

ABSTRACT

Rare diseases affect 10% of the first-world population, yet over 95% lack even a single pharmaceutical treatment. In the present age of information, we need ways to leverage our vast data and knowledge to streamline therapeutic development and lessen this gap. Here, we develop and implement an innovative informatic approach to identify therapeutic molecules, using the Connectivity Map and LINCS L1000 databases and disease-associated transcriptional signatures and pathways. We apply this to cystic fibrosis (CF), the most common genetic disease in people of northern European ancestry leading to chronic lung disease and reduced lifespan. We selected and tested 120 small molecules in a CF cell line, finding 8 with activity, and confirmed 3 in primary CF airway epithelia. Although chemically diverse, the transcriptional profiles of the hits suggest a common mechanism associated with the unfolded protein response and/or TNFα signaling. This study highlights the power of informatics to help identify new therapies and reveal mechanistic insights while moving beyond target-centric drug discovery.


Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/genetics , Genomics , Humans
13.
Sci Rep ; 10(1): 20553, 2020 11 25.
Article in English | MEDLINE | ID: mdl-33239626

ABSTRACT

Cystic fibrosis (CF), caused by mutations to CFTR, leads to severe and progressive lung disease. The most common mutant, ΔF508-CFTR, undergoes proteasomal degradation, extinguishing its anion channel function. Numerous in vitro interventions have been identified to partially rescue ΔF508-CFTR function yet remain poorly understood. Improved understanding of both the altered state of CF cells and the mechanisms of existing rescue strategies could reveal novel therapeutic strategies. Toward this aim, we measured transcriptional profiles of established temperature, genetic, and chemical interventions that rescue ΔF508-CFTR and also re-analyzed public datasets characterizing transcription in human CF vs. non-CF samples from airway and whole blood. Meta-analysis yielded a core disease signature and two core rescue signatures. To interpret these through the lens of prior knowledge, we compiled a "CFTR Gene Set Library" from literature. The core disease signature revealed remarkably strong connections to genes with established effects on CFTR trafficking and function and suggested novel roles of EGR1 and SGK1 in the disease state. Our data also revealed an unexpected mechanistic link between several genetic rescue interventions and the unfolded protein response. Finally, we found that C18, an analog of the CFTR corrector compound Lumacaftor, induces almost no transcriptional perturbation despite its rescue activity.


Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/genetics , Bronchi/metabolism , Cell Line , Computational Biology/methods , Databases, Genetic , Gene Expression/genetics , Gene Expression Profiling/methods , Genomics/methods , Humans , Mutation , Protein Transport/genetics , Transcriptome/genetics
14.
Hum Mol Genet ; 27(24): 4303-4314, 2018 12 15.
Article in English | MEDLINE | ID: mdl-30239724

ABSTRACT

Polyglutamine (polyQ) repeat diseases are a class of neurodegenerative disorders caused by CAG-repeat expansion. There are diverse cellular mechanisms behind the pathogenesis of polyQ disorders, including transcriptional dysregulation. Interestingly, we find that levels of the long isoform of nuclear paraspeckle assembly transcript 1 (Neat1L) are elevated in the brains of mouse models of spinocerebellar ataxia types 1, 2, 7 and Huntington's disease (HD). Neat1L was also elevated in differentiated striatal neurons derived from HD knock-in mice and in HD patient brains. The elevation was mutant Huntingtin (mHTT) dependent, as knockdown of mHTT in vitro and in vivo restored Neat1L to normal levels. In additional studies, we found that Neat1L is repressed by methyl CpG binding protein 2 (MeCP2) by RNA-protein interaction but not by occupancy of MeCP2 at its promoter. We also found that NEAT1L overexpression protects from mHTT-induced cytotoxicity, while reducing it enhanced mHTT-dependent toxicity. Gene set enrichment analysis of previously published RNA sequencing data from mouse embryonic fibroblasts and cells derived from HD patients shows that loss of NEAT1L impairs multiple cellular functions, including pathways involved in cell proliferation and development. Intriguingly, the genes dysregulated in HD human brain samples overlap with pathways affected by a reduction in NEAT1, confirming the correlation of NEAT1L and HD-induced perturbations. Cumulatively, the role of NEAT1L in polyQ disease model systems and human tissues suggests that it may play a protective role in CAG-repeat expansion diseases.


Subject(s)
Huntington Disease/genetics , Methyl-CpG-Binding Protein 2/genetics , RNA, Long Noncoding/genetics , Spinocerebellar Ataxias/genetics , Alternative Splicing/genetics , Animals , Cell Differentiation/genetics , Corpus Striatum/metabolism , Corpus Striatum/pathology , Gene Knock-In Techniques , Humans , Huntingtin Protein/genetics , Huntington Disease/physiopathology , Mice , Neurons/metabolism , Neurons/pathology , Peptides/genetics , Promoter Regions, Genetic , Protein Isoforms/genetics , RNA-Binding Proteins/genetics , Spinocerebellar Ataxias/physiopathology , Trinucleotide Repeat Expansion/genetics
15.
J Spine Surg ; 4(2): 423-432, 2018 Jun.
Article in English | MEDLINE | ID: mdl-30069538

ABSTRACT

Spine pathology afflicts people across the globe and is responsible for a large portion of physician visits and healthcare costs. Imaging such as plain radiographs, CT, MRI, and ultrasound is vital to assess structure, function, and stability of the spine and also provide guidance in therapeutic interventions. Ultrasound utilization in spine conditions is less ubiquitous, but provides benefits in low costs, portability, and dynamic imaging. This study assesses ultrasound efficacy in diagnosis and therapeutic interventions for spine pathology. A systematic review conducted via PubMed, MEDLINE, and Google Scholar identified 3,630 papers with eventual inclusion of 73 papers with an additional 21 papers supplemental papers subsequently added. Findings highlighted ultrasound utilization for different structural elements of the spine such as muscle, bone, disc, ligament, canal, and joints are presented and compared with radiographs, CT, and MRI imaging where relevant. Spinal curvature and mobility are similarly presented. Ultrasound efficacy for guided therapeutics about the spine is presented and assessed against other modalities. Ultrasound is a widely used and efficacious modality to guide injections about the spine. Diagnostic utility is less well studied, but shows promise in assessing fractures, posterior ligamentous stability, and intra-operative hardware placement. The low cost, portability, and dynamic imaging ability make it an attractive modality particularly for developing health systems and resource limited environments such as combat settings and the International Space Station. Further study is recommended before broad adoption in diagnostics.

16.
J Spine Surg ; 4(2): 433-445, 2018 Jun.
Article in English | MEDLINE | ID: mdl-30069539

ABSTRACT

Spaceflight alters normal physiology of cells and tissues observed on Earth. The effects of spaceflight on the musculoskeletal system have been thoroughly studied, however, the effects on cartilage have not. This area is gaining more relevance as long duration missions, such as Mars, are planned. The impact on intervertebral discs and articular cartilage are of particular interest to astronauts and their physicians. This review surveys the literature and reports on the current body of knowledge regarding the effects of spaceflight on cartilage, and specifically changes to the spine and intervertebral disc integrity and physiology. A systematic literature review was conducted using PubMed, MEDLINE, and Google Scholar. Eighty-six unique papers were identified, 15 of which were included. The effect of spaceflight on cartilage is comprehensively presented due to limited research on the effect of microgravity on the spine/intervertebral discs. Cellular, animal, and human studies are discussed, focusing on human physiologic changes, cartilage histology, mineralization, biomechanics, chondrogenesis, and tissue engineering. Several common themes were found, such as decreased structural integrity of intervertebral disks and impaired osteogenesis/ossification. However, studies also presented conflicting results, rendering strong conclusions difficult. The paucity of human cartilage studies in spaceflight leaves extrapolation from other model systems the only current option for drawing conclusions despite known and unknown limitations in applicability to human physiology, especially spinal pathophysiology which is special interest. The aerospace and biomedical research communities would benefit from further human spaceflight articular cartilage and intervertebral disc studies. Further research may yield beneficial application for spaceflight, and crossover in understanding and treating terrestrial diseases like osteoarthritis and vertebral disc degeneration.

17.
Neurobiol Dis ; 115: 182-193, 2018 07.
Article in English | MEDLINE | ID: mdl-29660499

ABSTRACT

The neuronal ceroid lipofuscinoses are a class of inherited neurodegenerative diseases characterized by the accumulation of autofluorescent storage material. The most common neuronal ceroid lipofuscinosis has juvenile onset with rapid onset blindness and progressive degeneration of cognitive processes. The juvenile form is caused by mutations in the CLN3 gene, which encodes the protein CLN3. While mouse models of Cln3 deficiency show mild disease phenotypes, it is apparent from patient tissue- and cell-based studies that its loss impacts many cellular processes. Using Cln3 deficient mice, we previously described defects in mouse brain endothelial cells and blood-brain barrier (BBB) permeability. Here we expand on this to other components of the BBB and show that Cln3 deficient mice have increased astrocyte endfeet area. Interestingly, this phenotype is corrected by treatment with a commonly used GAP junction inhibitor, carbenoxolone (CBX). In addition to its action on GAP junctions, CBX has also been proposed to alter lipid microdomains. In this work, we show that CBX modifies lipid microdomains and corrects membrane fluidity alterations in Cln3 deficient endothelial cells, which in turn improves defects in endocytosis, caveolin-1 distribution at the plasma membrane, and Cdc42 activity. In further work using the NIH Library of Integrated Network-based Cellular Signatures (LINCS), we discovered other small molecules whose impact was similar to CBX in that they improved Cln3-deficient cell phenotypes. Moreover, Cln3 deficient mice treated orally with CBX exhibited recovery of impaired BBB responses and reduced autofluorescence. CBX and the compounds identified by LINCS, many of which have been used in humans or approved for other indications, may find therapeutic benefit in children suffering from CLN3 deficiency through mechanisms independent of their original intended use.


Subject(s)
Membrane Fluidity/physiology , Membrane Glycoproteins/genetics , Molecular Chaperones/genetics , Neuronal Ceroid-Lipofuscinoses/genetics , Phenotype , Animals , Cell Line, Transformed , Female , Male , Membrane Glycoproteins/deficiency , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Neuronal Ceroid-Lipofuscinoses/metabolism , Neuronal Ceroid-Lipofuscinoses/pathology
18.
J Biol Chem ; 291(49): 25489-25504, 2016 Dec 02.
Article in English | MEDLINE | ID: mdl-27756846

ABSTRACT

We previously reported that delivery of a microRNA-138 mimic or siRNA against SIN3A to cultured cystic fibrosis (ΔF508/ΔF508) airway epithelia partially restored ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR)-mediated cAMP-stimulated Cl- conductance. We hypothesized that dissecting this microRNA-138/SIN3A-regulated gene network would identify individual proteins contributing to the rescue of ΔF508-CFTR function. Among the genes in the network, we rigorously validated candidates using functional CFTR maturation and electrolyte transport assays in polarized airway epithelia. We found that depletion of the ubiquitin ligase SYVN1, the ubiquitin/proteasome system regulator NEDD8, or the F-box protein FBXO2 partially restored ΔF508-CFTR-mediated Cl- transport in primary cultures of human cystic fibrosis airway epithelia. Moreover, knockdown of SYVN1, NEDD8, or FBXO2 in combination with corrector compound 18 further potentiated rescue of ΔF508-CFTR-mediated Cl- conductance. This study provides new knowledge of the CFTR biosynthetic pathway. It suggests that SYVN1 and FBXO2 represent two distinct multiprotein complexes that may degrade ΔF508-CFTR in airway epithelia and identifies a new role for NEDD8 in regulating ΔF508-CFTR ubiquitination.


Subject(s)
Amino Acid Sequence , Cell Cycle Proteins/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Epithelial Cells/metabolism , F-Box Proteins/metabolism , Nerve Tissue Proteins/metabolism , Proteasome Endopeptidase Complex/metabolism , Proteolysis , Respiratory Mucosa/metabolism , Sequence Deletion , Ubiquitin-Protein Ligases/metabolism , Ubiquitination , Ubiquitins/metabolism , Cell Cycle Proteins/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Epithelial Cells/pathology , F-Box Proteins/genetics , Gene Knockdown Techniques , HeLa Cells , Humans , Ion Transport/genetics , NEDD8 Protein , Nerve Tissue Proteins/genetics , Proteasome Endopeptidase Complex/genetics , Respiratory Mucosa/physiology , Ubiquitin/genetics , Ubiquitin/metabolism , Ubiquitin-Protein Ligases/genetics
19.
Hum Mol Genet ; 25(16): 3454-3466, 2016 08 15.
Article in English | MEDLINE | ID: mdl-27378699

ABSTRACT

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG expansion in the gene-encoding Huntingtin (HTT). Transcriptome dysregulation is a major feature of HD pathogenesis, as revealed by a large body of work on gene expression profiling of tissues from human HD patients and mouse models. These studies were primarily focused on transcriptional changes affecting steady-state overall gene expression levels using microarray based approaches. A major missing component, however, has been the study of transcriptome changes at the post-transcriptional level, such as alternative splicing. Alternative splicing is a critical mechanism for expanding regulatory and functional diversity from a limited number of genes, and is particularly complex in the mammalian brain. Here we carried out a deep RNA-seq analysis of the BA4 (Brodmann area 4) motor cortex from seven human HD brains and seven controls to systematically discover aberrant alternative splicing events and characterize potential associated splicing factors in HD. We identified 593 differential alternative splicing events between HD and control brains. Using two expanded panels with a total of 108 BA4 tissues from patients and controls, we identified four splicing factors exhibiting significantly altered expression levels in HD patient brains. Moreover, follow-up molecular analyses of one splicing factor PTBP1 revealed its impact on disease-associated splicing patterns in HD. Collectively, our data provide genomic evidence for widespread splicing dysregulation in HD brains, and suggest the role of aberrant alternative splicing in the pathogenesis of HD.


Subject(s)
Heterogeneous-Nuclear Ribonucleoproteins/genetics , Huntington Disease/genetics , Motor Cortex/metabolism , Polypyrimidine Tract-Binding Protein/genetics , Transcriptome/genetics , Adult , Aged , Alternative Splicing/genetics , Animals , Autopsy , Female , Gene Expression Regulation , Genetic Predisposition to Disease , Heterogeneous-Nuclear Ribonucleoproteins/biosynthesis , High-Throughput Nucleotide Sequencing , Humans , Huntingtin Protein/genetics , Huntington Disease/physiopathology , Male , Mice , Middle Aged , Motor Cortex/pathology , Polypyrimidine Tract-Binding Protein/biosynthesis
20.
Am J Respir Crit Care Med ; 194(7): 845-854, 2016 10 01.
Article in English | MEDLINE | ID: mdl-27027566

ABSTRACT

RATIONALE: Studies suggest that inappropriate responses to proinflammatory stimuli might contribute to inflammation in cystic fibrosis (CF) lungs. However, technical challenges have made it difficult to distinguish whether altered responses in CF airways are an intrinsic defect or a secondary effect of chronic disease in their tissue of origin. The CF pig model provides an opportunity to study the inflammatory responses of CF airways at birth, before the onset of infection and inflammation. OBJECTIVES: To test the hypothesis that acute inflammatory responses are perturbed in porcine CF airways. METHODS: We investigated the inflammatory responses of newborn CF and non-CF pig airways following a 4-hour exposure to heat-killed Staphylococcus aureus, in vivo and in vitro. MEASUREMENTS AND MAIN RESULTS: Following an in vivo S. aureus challenge, markers of inflammation were similar between CF and littermate control animals through evaluation of bronchoalveolar lavage and tissues. However, transcriptome analysis revealed genotype-dependent differences as CF pigs showed a diminished host defense response compared with their non-CF counterparts. Furthermore, CF pig airways exhibited an increase in apoptotic pathways and a suppression of ciliary and flagellar biosynthetic pathways. Similar differences were observed in cultured airway epithelia from CF and non-CF pigs exposed to the stimulus. CONCLUSIONS: Transcriptome profiling suggests that acute inflammatory responses are dysregulated in the airways of newborn CF pigs.


Subject(s)
Cystic Fibrosis/immunology , Lung/immunology , Staphylococcus aureus/immunology , Animals , Animals, Newborn , Apoptosis/genetics , Cell Proliferation/genetics , Cystic Fibrosis/genetics , Cystic Fibrosis/microbiology , Disease Progression , Epithelium/immunology , Genotype , In Vitro Techniques , Inflammation/genetics , Inflammation/immunology , Models, Animal , Respiratory Mucosa/immunology , Signal Transduction/genetics , Swine , Transcriptome/genetics
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