Sports and Recreation-Related Wrist Fractures: An Epidemiological Study.

Background Wrist fractures have increased over the past several decades. The objective of this study was to identify all-cause and sports-related incidence rates of wrist fractures presenting to emergency departments (EDs) in the United States (U.S.) from 2013 to 2022. A secondary aim of the study was to identify if wrist fractures significantly decreased during 2020. Methodology The National Electronic Injury Surveillance System database was queried to identify the number of wrist fractures presenting to U.S. EDs from 2013 to 2022. Incidence rates in 100,000 person-years were calculated by sport, age, sex, and year. Results From 2013 to 2022, there were 2,027,131 wrist fractures evaluated at U.S. EDs. Injuries peaked in the 10-14-year-old age group, followed by the 5-9 and 85+-year-old age groups. In total, 1,096,598 were sustained during sports and recreation. Cycling, playgrounds, and skateboarding were the leading sports and recreation-related activities. Sports-related wrist fractures followed a unimodal distribution peaking in the 10-14-year-old age group. Females sustained 52% of wrist fractures overall but only 39% of sports-related wrist fractures. All-terrain vehicle and skateboarding-related wrist fractures significantly increased over the study period. Playground and soccer-related wrist fractures significantly decreased in 2020. Conclusions All-cause wrist fractures presenting to U.S. EDs significantly increased from 2013 to 2022 though sports-related wrist fractures did not. Pediatric males and elderly females are most at risk for wrist fractures overall while sports-related wrist fractures predominate in the pediatric population. Youth sports and recreation officials should be aware of the risks to mitigate the incidence of sports-related wrist fractures.

CHOP-mediated IL-23 overexpression does not drive colitis in experimental spondyloarthritis.

HLA-B27 is a major risk factor for spondyloarthritis (SpA), yet the underlying mechanisms remain unclear. HLA-B27 misfolding-induced IL-23, which is mediated by endoplasmic reticulum (ER) stress has been hypothesized to drive SpA pathogenesis. Expression of HLA-B27 and human ß2m (hß2m) in rats (HLA-B27-Tg) recapitulates key SpA features including gut inflammation. Here we determined whether deleting the transcription factor CHOP (Ddit3-/-), which mediates ER-stress induced IL-23, affects gut inflammation in HLA-B27-Tg animals. ER stress-mediated Il23a overexpression was abolished in CHOP-deficient macrophages. Although CHOP-deficiency also reduced Il23a expression in immune cells isolated from the colon of B27+ rats, Il17a levels were not affected, and gut inflammation was not reduced. Rather, transcriptome analysis revealed increased expression of pro-inflammatory genes, including Il1a, Ifng and Tnf in HLA-B27-Tg colon tissue in the absence of CHOP, which was accompanied by higher histological Z-scores. RNAScope localized Il17a mRNA to the lamina propria of the HLA-B27-Tg rats and revealed similar co-localization with Cd3e (CD3) in the presence and absence of CHOP. This demonstrates that CHOP-deficiency does not improve, but rather exacerbates gut inflammation in HLA-B27-Tg rats, indicating that HLA-B27 is not promoting gut disease through ER stress-induced IL-23. Hence, CHOP may protect rats from more severe HLA-B27-induced gut inflammation.

Orthopedic Surgery Residency Program Rankings and Gender Diversity.

Background Orthopedic surgery residency programs are some of the least gender-diverse specialty programs in medicine. Despite strong representation at the undergraduate and medical school levels and increased applications to orthopedic surgery residency programs by women, there is still a substantial gender gap at the resident level. This study explores the relationship between the gender diversity of orthopedic surgery residency programs and program rankings. Methodology Program rank, program director gender identity, and gender diversity data were collected for the top 100 programs by reputation in Doximity. Gender diversity was measured as the proportion of female residents in the program and alumni. Results The greatest percentage of women in a program was 33% and the smallest was 3%. After linear regression analysis, we found that there was a statistically significant positive correlation between program rank and the proportion of women. The higher ranked a program was, the greater the proportion of women. There was no significant correlation between program director gender, appointment year, and program rank. Conclusions These results suggest that, although there is still a long way to go before closing the gender gap in orthopedic surgery residency programs, higher-ranked programs are associated with greater gender diversity than their lower-ranked counterparts.

Distal Radius Fracture Therapy Utilization Following Traditional Open Reduction and Internal Fixation and Dorsal Bridge Plate Fixation.

Background Many distal radius fractures are treated with a volar locking plate, but a minority undergo dorsal bridge plate fixation. This study's primary purpose was to compare therapy utilization following distal radius fractures treated with traditional open reduction and internal fixation (ORIF) versus dorsal bridge plate fixation. Secondary outcomes were time to first and last therapy visits and therapy costs. Methods Patients over 18 years old who underwent distal radius ORIF between January 2021 and August 2022 at a single regional orthopedic practice were identified. Patients who underwent post-operative hardware removal were retrospectively reviewed to identify dorsal bridge plate fixation patients. This resulted in "traditional ORIF" and "dorsal bridge plate" groups. Therapy visit number, cost, and payor (insurance type including Medicare, private insurance, worker's compensation, automobile policy, and private pay) were collected. Results In total, 1,376 patients met the inclusion criteria. Of these, 713 of the 1,283 (55.6%) patients in the traditional ORIF group and 25 of the 44 patients (56.8%) in the dorsal bridge plate group attended therapy at our institution. Traditional ORIF and dorsal bridge plate patients averaged 12.6(±10) and 24(±18.7) therapy visits in the one-year following ORIF, respectively. Time to last therapy visit was 90.9(±60) and 175.2(±72.1) days in the traditional ORIF and dorsal bridge plate groups, respectively. Total therapy cost was $1,219(±$1,314) and $2,015(±$1,828) in the traditional ORIF and dorsal bridge plate groups with similar out-of-pocket costs. Conclusions Dorsal bridge plate fixation patients attended a greater number of therapy sessions, had a longer time from surgery until therapy end, and had a higher therapy total cost relative to traditional ORIF, but both groups had similar patient out-of-pocket therapy costs.

The Most Impactful Articles on the Shoulder Labrum From the United States or Europe, and Decreased Level of Evidence Is Associated With Increased Altmetric Attention Score.

Purpose: To use the top 100 articles pertaining to the shoulder labrum to understand the impact that social medial platforms have on the dissemination of shoulder research and to highlight bibliometric factors associated with Altmetric Attention Scores (AAS) to offer insight into the impact that social media platforms have on the dissemination, attention, and citation of shoulder research publications. Methods: This was a cross-sectional study. In January 2023, the Altmetric database was searched using the PubMed Medical Subject Headings terms "shoulder labrum." Articles with the greatest AAS were screened to exclude other topics unrelated to the labrum of the shoulder. The top 100 articles that met inclusion criteria were used in the final analysis. Bibliometric factors pertaining to each study were collected for further analysis of article characteristics in accordance with previous studies. Results: The Altmetric Database query yielded 619 studies. The top 100 articles with highest AAS were identified, mean Attestation Score was 24.85 ± 55.51, with a range of 7 to 460. The included articles represented 35 journals, with 57 articles attributed to 3 journals: American Journal of Sports Medicine (AJSM; 29%), Arthroscopy: The Journal of Arthroscopic & Related Surgery (Arthroscopy; 19%), and the Journal of Shoulder and Elbow Surgery (JSES; 9%). There was a significant increase in AAS for every decrease in the numerical Level of Evidence value for a study (P = .011) but no association between score and citation rate (P > 005). Conclusions: Top articles on the shoulder labrum, as defined by high AAS score, are most commonly original clinical research published in 1 of 3 sports medicine journals and performed in the United States or Europe. A decreased numerical Level of Evidence is associated with an increase in AAS score, but there is no association between AAS score and citation rate. Clinical Relevance: The increasing amount of science and health information shared freely through open-access journals, online servers, and numerous social media channels makes it difficult to measure the impact of research. Using measures such as the Altmetric Attention Score, in isolation or addition to measures of researcher or journal impact, has the potential to provide comprehensive information about the impact of research in the modern world.

Attritional Extensor Digiti Minimi Tendon Rupture Associated With a Distal Ulna Fracture.

Attritional extensor tendon ruptures are common in the setting of arthritis but, to our knowledge, have never previously been reported in the setting of a distal ulna fracture. This case report describes a 56-year-old male patient who sustained a left-hand dog bite resulting in crush injuries to the thumb and ring finger and a minimally displaced distal ulna fracture. The patient initially underwent appropriate surgical intervention for the thumb and finger crush injuries and non-operative management of the distal ulna fracture with splint immobilization. He experienced an extensor digiti minimi tendon (EDM) rupture two and a half weeks post-operatively. Radiographs demonstrated interval distal ulna fracture displacement with a prominent dorsal spike and absence of arthritis. He subsequently underwent distal ulna open reduction internal fixation and an extensor indicis proprius (EIP) to EDM tendon transfer. This case demonstrates a novel complication following non-operative management of a distal ulna fracture in which the prominent dorsal distal ulna resulted in direct irritation to the extensor tendon and subsequent attritional extensor tendon rupture. This potential complication should be considered in determining appropriate treatment for distal ulna fractures.

All-Inside Versus Outside-in Repair of Triangular Fibrocartilage Complex Peripheral Tears.

PURPOSE: Triangular fibrocartilage complex (TFCC) peripheral tears with persistent wrist pain can be treated with arthroscopic surgical repair owing to vascularization of the peripheral region. The safety and efficacy of all-inside repair has been shown in prior case series. The purpose of this study was to compare two methods of arthroscopic peripheral TFCC repair: all-inside vertical mattress and outside-in horizontal mattress. METHODS: A 5-year retrospective review was performed on patients treated from 2016 to 2021 with wrist arthroscopy and TFCC repair for Palmer 1B tears. Patients with ulnar extrinsic ligament repair, distal radioulnar joint instability, concomitant ulnar shortening osteotomy, and extensor carpi ulnaris instability were excluded. Patient therapy and office visit records were reviewed. Outcomes including Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH); range of motion; grip strength; immobilization time; complications; and need for revision procedures were compared. RESULTS: Fifty-two patients were included in the study, 32 in the outside-in group and 20 in the all-inside group. The average follow-up length was 24.8 weeks, with similar range of motion and strength in both groups. The average postoperative QuickDASH score was 13 in the outside-in group and 9 in the all-inside group at 43.5 months, compared with the preoperative QuickDASH scores of 47 and 50, respectively. Mean immobilization time was longer for outside-in than for all-inside (5.25 vs 2.0 weeks, respectively). CONCLUSIONS: All-inside arthroscopic peripheral TFCC repair showed range of motion, grip strength, complications, revisions, and postoperative improvement in QuickDASH scores similar to those with the outside-in technique. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV; retrospective comparative study.

A Young Skier with Leg Pain.

BACKGROUND: Proximal tibiofibular joint (PTFJ) dislocation is a rare injury that can disrupt the proximal tibia-fibula joint. The abnormalities in knee x-ray imaging can be subtle and difficult to detect, requiring careful assessment. This rare cause of lateral knee pain requires a high level of suspicion for diagnosis. Treatment is closed reduction; unstable PTFJ dislocations often require surgical intervention. CASE REPORT: A 17-year-old young man presented to the emergency department (ED) with right lateral knee pain and difficulty walking after colliding with another skier 2 days prior. The examination showed right lateral ecchymosis and tenderness over the lateral proximal fibula. He remained neurovascularly intact with a full passive and active range of motion. X-ray studies were obtained. The patient was referred by his outpatient orthopedic surgeon after the initial knee x-ray study was concerning for PTFJ dislocation and unsuccessful reduction. In the ED, the patient underwent moderate sedation and successful orthopedic-guided reduction via medial force on the lateral fibular head, while hyper-flexing the knee and holding the foot dorsiflexed and everted. Post-reduction radiographs showed improved proximal tibiofibular alignment without fracture. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: PTFJ dislocation is a rare injury that can be missed easily and requires a high level of suspicion when presented with an acute traumatic knee pain. Closed reduction of PTFJ dislocation can be achieved in the ED and early identification can prevent long-term sequelae.

Erratum to "Hand Surgery Patient Perspectives on Medical Cannabis: A Survey of Over 600 Patients" [Journal of Hand Surgery Global Online 5 (2023) 102-107].

[This corrects the article DOI: 10.1016/j.jhsg.2022.02.009.].

Analysis of Orthopaedic In-Training Examination Trauma Questions: 2017 to 2021.

INTRODUCTION: The Orthopaedic In-Training Examination (OITE) is a multiple-choice examination developed by the American Academy of Orthopaedic Surgeons annually since 1963 to assess orthopaedic residents' knowledge. This study's purpose is to analyze the 2017 to 2021 OITE trauma questions to aid orthopaedic residents preparing for the examination. METHODS: The 2017 to 2021 OITEs on American Academy of Orthopaedic Surgeons' ResStudy were retrospectively reviewed to identify trauma questions. Question topic, references, and images were analyzed. Two independent reviewers classified each question by taxonomy. RESULTS: Trauma represented 16.6% (204/1,229) of OITE questions. Forty-nine percent of trauma questions included images (100/204), 87.0% (87/100) of which contained radiographs. Each question averaged 2.4 references, of which 94.9% were peer-reviewed articles and 46.8% were published within 5 years of the respective OITE. The most common taxonomic classification was T1 (46.1%), followed by T3 (37.7%) and T2 (16.2%). DISCUSSION: Trauma represents a notable portion of the OITE. Prior OITE trauma analyses were published greater than 10 years ago. Since then, there has been an increase in questions with images and requiring higher cognitive processing. The Journal of Orthopaedic Trauma (24.7%), Journal of the American Academy of Orthopaedic Surgeons (10.1%), and Journal of Bone and Joint Surgery, American Volume (9.3%) remain the most cited sources.

Hand Surgery Patient Perspectives on Medical Cannabis: A Survey of Over 600 Patients.

Purpose: Medical cannabis (MC) has been proposed as a potential addition to multimodal pain management regimens in orthopedics. This study evaluates hand and upper-extremity patient perspectives of MC as a treatment for common orthopedic and musculoskeletal pain conditions. This study also aims to identify the proportion of patients already using MC, perceived barriers to MC use, and opinions on insurance coverage and legality of cannabis. Methods: An anonymous cross-sectional survey study was conducted of all patients at least 18 years old presenting from October 2020 to January 2021 to a hand and upper-extremity outpatient clinic. The survey collected information regarding opinion on MC, including use, legality, and willingness to use MC in the future. Medical cannabis was legal in the states where the study was conducted. Results: A total of 679 patients completed the survey (response rate 72.5%). Sixty-eight patients (10.0%) reported currently using MC. Of the 623 patients (90.0%) who reported not currently using MC, 504 (80.9%) would consider using MC for chronic pain, while the remaining 119 (19.1%) would not consider the use of MC for chronic pain. Age was not associated with whether a patient would consider using MC (P = .16) or was already using MC (P = .10). The most identified barrier to MC use was cost, reported as either expensive or not affordable by 477 patients (70.5%). Conclusions: This study found that most patients presenting for hand and upper-extremity complaints would consider using MC (80.9%), and most perceive it as a safe treatment option for common orthopedic conditions. Moreover, 10% of patients reported already using MC. One of the major barriers to MC use is the cost. Most (90.9%) patients support policies for legalization and insurance coverage of MC. Type of study/level of evidence: Therapeutic Level III.

Trochlear Dysplasia as Shown by Increased Sulcus Angle Is Associated With Osteochondral Damage in Patients With Patellar Instability.

PURPOSE: The primary study objective was to describe the incidence of osteochondral damage (OD) in our cohort of patients with patellar instability (PI). The secondary objective was to assess for associations between patient demographic characteristics, duration of PI, and quantitative radiographic measurements of anatomic risk factors for PI and OD in this cohort. METHODS: A retrospective chart review identified patients treated for PI at a tertiary referral center between 2013 and 2018. Patients were evaluated for osteochondral injury with either magnetic resonance imaging if treated nonoperatively or operative reports if treated surgically. The Caton-Deschamps ratio, proximal tibial tubercle-to-trochlear groove (pTT-TG) distance, distal tibial tubercle-to-trochlear groove (dTT-TG) distance, lateral trochlear inclination (LTI) angle, lateral patellar inclination (LPI) angle, and sulcus angle were calculated from magnetic resonance imaging scans. Trochlear dysplasia is an important risk factor for PI that can be reliability quantified by the pTT-TG distance, dTT-TG distance, LTI angle, sulcus angle, and LPI angle. Demographic data including age at first instability event, sex, body mass index, symptom duration, and number of dislocations were documented. RESULTS: A total of 125 knees in 118 patients (average age, 13.9 ± 3.4 years; 48% female patients) with PI were identified. Within this cohort, 67% were treated surgically and 53% had OD. No association was identified between osteochondral injury and age, sex, body mass index, symptom duration, LTI angle, LPI angle, dTT-TG distance, pTT-TG distance, or number of dislocations. An increased sulcus angle (more dysplasia) showed a statistically significant association with osteochondral pathology (P = .021), and higher sulcus angles were statistically significantly associated with acute osteochondral fracture compared with chondral injury (P = .001). CONCLUSIONS: Using quantitative analysis of trochlear dysplasia, this study identified a significant association between trochlear dysplasia (sulcus angle) and the incidence of OD in our cohort of patients with PI. The frequency of dislocation or subluxation and patient demographic characteristics were not significantly associated with OD. LEVEL OF EVIDENCE: Level III, retrospective prognostic study.

Confirming Proper Button Deployment of Suspensory Fixation During ACL Reconstruction.

BACKGROUND: Suspensory fixation of anterior cruciate ligament (ACL) reconstruction (ACLR) grafts has emerged as a popular device for femoral graft fixation. However, improper deployment of the suspensory fixation can compromise proper graft tensioning, leading to failure and revision. Also, soft tissue interposition between the button and bone has been associated with graft migration and pain, occasionally requiring revision surgery. Many surgeons rely on manual testing and application of distal tension to the graft to confirm proper button deployment on the lateral cortex of the femur for ACL graft fixation. PURPOSE: To determine the reliability of the manual resistance maneuver when applying distal tension to deploy the suspensory device along the lateral cortex of the femur. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: All patients undergoing ACLR with a suture button suspensory device for femoral fixation were eligible for enrollment in the study. The surgeries were performed by 3 board-certified, sports medicine fellowship-trained orthopaedic surgeons at a single outpatient surgical center between May 2018 and June 2019. All grafts were passed in a retrograde manner into the femoral tunnel, and a vigorous manual tensioning maneuver in a distal direction was placed on the graft to deploy and secure along the lateral cortex of the femur. Intraoperative mini c-arm fluoroscopy was obtained to demonstrate proper suture button positioning. If interposing tissue or an improperly flipped button was identified, rectifying steps were undertaken and recorded. RESULTS: A total of 51 patients with a mean age of 33.3 years were included in the study. Of these patients, 74.5% had normal suture button positioning identified via intraoperative fluoroscopic imaging, while 15.7% had interposed soft tissue and 9.8% had an improperly flipped button. In all cases, the surgeon was able to rectify the malpositioning intraoperatively. CONCLUSION: Despite the manual sensation of proper suspensory button positioning, intraoperative fluoroscopy identified suture button deployment errors in ACLR 25% of the time. Correcting the malpositioning is not technically demanding. These findings advocate for routine intraoperative surveillance to confirm appropriate suture button seating during ACLR.

Patient-Reported Outcomes, Return-to-Sport Status, and Reinjury Rates After Anterior Cruciate Ligament Reconstruction in Adolescent Athletes: Minimum 2-Year Follow-up.

BACKGROUND: Significant variation exists in the published rates of return to sport after anterior cruciate ligament (ACL) reconstruction (ACLR). Functional outcomes and psychological response to injury have been implicated as factors that influence return to sport. Most studies focus on patients aged in the mid-20s, and less is known about this topic in adolescents. PURPOSE: To report midterm ACLR results for adolescent patients with regard to return to primary sport, patient-reported outcomes, and reinjury rate. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Adolescent athletes were contacted at a minimum of 2 years after ACLR. Patients completed 2 patient-reported outcome measures, the ACL--Return to Sport After Injury (ACL-RSI) and the International Knee Documentation Committee (IKDC) subjective form, and responded to questions regarding preinjury primary sport and level of competition, post-ACLR return to primary sport status, and reinjury. RESULTS: A total of 74 patients (mean ± SD surgical age, 15.9 ± 1.5 years; follow-up age, 19.9 ± 2.0 years; response rate, 24.5%) completed the surveys at a mean of 4.0 ± 2.0 years after primary ACLR. Outcome scores averaged 90.3 ± 12.3 for IKDC and 81.6 ± 20.4 for ACL-RSI. Questionnaire responses indicated that 27.0% of patients did not return to or sustain primary sport participation after ACLR; the principal reasons were poor knee function, team/training change, and fear of another injury. Both IKDC and ACL-RSI scores were statistically lower in patients who did not successfully return to their primary sport in contrast to patients who successfully resumed their primary sport (IKDC, P = .026; ACL-RSI, P < .001). IKDC and ACL-RSI scores were moderately positively correlated with one another (r Spearman = 0.60). There were 18 patients (reinjury rate, 24.3%) who suffered another ACL injury; 8 of these injuries included ipsilateral ACL graft tear (retear rate, 10.8%). CONCLUSION: In our cohort, 73% of adolescent patients successfully returned to their primary preinjury sport at a minimum of 2 years after ACLR. Both knee function and psychological responses to injury were important in determining an adolescent athlete's return to sport. The findings support the use of the IKDC and ACL-RSI at midterm follow-up, with higher scores associated with a greater likelihood of adolescent patients returning to sport after ACLR.

Zeb2 Is a Regulator of Astrogliosis and Functional Recovery after CNS Injury.

The astrocytic response to injury is characterized on the cellular level, but our understanding of the molecular mechanisms controlling the cellular processes is incomplete. The astrocytic response to injury is similar to wound-healing responses in non-neural tissues that involve epithelial-to-mesenchymal transitions (EMTs) and upregulation in ZEB transcription factors. Here we show that injury-induced astrogliosis increases EMT-related genes expression, including Zeb2, and long non-coding RNAs, including Zeb2os, which facilitates ZEB2 protein translation. In mouse models of either contusive spinal cord injury or transient ischemic stroke, the conditional knockout of Zeb2 in astrocytes attenuates astrogliosis, generates larger lesions, and delays the recovery of motor function. These findings reveal ZEB2 as an important regulator of the astrocytic response to injury and suggest that astrogliosis is an EMT-like process, which provides a conceptual connection for the molecular and cellular similarities between astrogliosis and wound-healing responses in non-neural tissue.

Manipulating Adult Neural Stem and Progenitor Cells with G-Quadruplex Ligands.

G-quadruplexes are pervasive nucleic acid secondary structures in mammalian genomes and transcriptomes that regulate gene expression and genome duplication. Small molecule ligands that modify the stability of G-quadruplexes are widely studied in cancer, but whether G-quadruplex ligands can also be used to manipulate cell function under normal development and homeostatic conditions is largely unexplored. Here we show that two related G-quadruplex ligands (pyridostatin and carboxypyridostatin) can reduce proliferation of adult neural stem cell and progenitor cells derived from the adult mouse subventricular zone both in vitro and in vivo. Studies with neurosphere cultures show that pyridostatin reduces proliferation by a mechanism associated with DNA damage and cell death. By contrast, selectively targeting RNA G-quadruplex stability with carboxypyridostatin diminishes proliferation through a mechanism that promotes cell cycle exit and the production of oligodendrocyte progenitors. The ability to generate oligodendrocyte progenitors by targeting RNA G-quadruplex stability, however, is dependent on the cellular environment. Together, these findings show that ligands that can selectively stabilize RNA G-quadruplexes are an important, new class of molecular tool for neural stem and progenitor cell engineering, whereas ligands that target DNA G-quadruplexes have limited utility due to their toxicity.

Conserved Upstream Regulatory Regions in Mammalian Tyrosine Hydroxylase.

Tyrosine hydroxylase (Th) encodes the rate-limiting enzyme in catecholamine biosynthesis, and the regulation of its transcription is critical for the specification and maintenance of catecholaminergic neuron phenotypes. For many genes, regulatory genomic DNA sequences that are upstream of the proximal promoter control expression levels as well as region-specific expression patterns. The regulatory architecture of the genomic DNA upstream of the Th proximal promoter, however, is poorly understood. In this study, we examined the 11 kb upstream nucleotide sequence of Th from nine mammalian species and identified five highly conserved regions. Using cultured human cells and mouse olfactory bulb tissue, chromatin immunoprecipitation (ChIP) assays show that these conserved regions recruit transcription factors that are established regulators of Th transcription (such as NURR1, PITX3, FOXA2, MEIS2, and PAX6). This analysis also identified a conserved binding site for CTCF, and functional studies in cultured human cells and ChIP assays with mouse tissue show that CTCF is a novel regulator of Th transcription in the forebrain. Together, the findings in this study provide key insights into the upstream regulatory genomic architecture and regulatory mechanisms controlling mammalian Th gene transcription.

Odorant Sensory Input Modulates DNA Secondary Structure Formation and Heterogeneous Ribonucleoprotein Recruitment on the Tyrosine Hydroxylase and Glutamic Acid Decarboxylase 1 Promoters in the Olfactory Bulb.

Adaptation of neural circuits to changes in sensory input can modify several cellular processes within neurons, including neurotransmitter biosynthesis levels. For a subset of olfactory bulb interneurons, activity-dependent changes in GABA are reflected by corresponding changes in Glutamate decarboxylase 1 (Gad1) expression levels. Mechanisms regulating Gad1 promoter activity are poorly understood, but here we show that a conserved G:C-rich region in the mouse Gad1 proximal promoter region both recruits heterogeneous nuclear ribonucleoproteins (hnRNPs) that facilitate transcription and forms single-stranded DNA secondary structures associated with transcriptional repression. This promoter architecture and function is shared with Tyrosine hydroxylase (Th), which is also modulated by odorant-dependent activity in the olfactory bulb. This study shows that the balance between DNA secondary structure formation and hnRNP binding on the mouse Th and Gad1 promoters in the olfactory bulb is responsive to changes in odorant-dependent sensory input. These findings reveal that Th and Gad1 share a novel transcription regulatory mechanism that facilitates sensory input-dependent regulation of dopamine and GABA expression.SIGNIFICANCE STATEMENT Adaptation of neural circuits to changes in sensory input can modify several cellular processes within neurons, including neurotransmitter biosynthesis levels. This study shows that transcription of genes encoding rate-limiting enzymes for GABA and dopamine biosynthesis (Gad1 and Th, respectively) in the mammalian olfactory bulb is regulated by G:C-rich regions that both recruit heterogeneous nuclear ribonucleoproteins (hnRNPs) to facilitate transcription and form single-stranded DNA secondary structures associated with repression. hnRNP binding and formation of DNA secondary structure on the Th and Gad1 promoters are mutually exclusive, and odorant sensory input levels regulate the balance between these regulatory features. These findings reveal that Th and Gad1 share a transcription regulatory mechanism that facilitates odorant-dependent regulation of dopamine and GABA expression levels.

Selective repression of gene expression in neuropathic pain by the neuron-restrictive silencing factor/repressor element-1 silencing transcription (NRSF/REST).

Neuropathic pain often develops following nerve injury as a result of maladaptive changes that occur in the injured nerve and along the nociceptive pathways of the peripheral and central nervous systems. Multiple cellular and molecular mechanisms likely account for these changes; however, the exact nature of these mechanisms remain largely unknown. A growing number of studies suggest that alteration in gene expression is an important step in the progression from acute to chronic pain states and epigenetic regulation has been proposed to drive this change in gene expression. In this review, we discuss recent evidence that the DNA-binding protein neuron-restrictive silencing factor/repressor element-1 silencing transcription factor (NRSF/REST) is an important component in the development and maintenance of neuropathic pain through its role as a transcriptional regulator for a select subset of genes that it normally represses during development.