Essential Role of XBP1 in Maintaining Photoreceptor Synaptic Integrity in Early Diabetic Retinopathy.

Purpose: Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults characterized by retinal dysfunction and neurovascular degeneration. We previously reported that deletion of X-box binding protein 1 (XBP1) leads to accelerated retinal neurodegeneration in diabetes; however, the mechanisms remain elusive. The goal of this study is to determine the role of XBP1 in the regulation of photoreceptor synaptic integrity in early DR. Methods: Diabetes was induced by streptozotocin in retina-specific XBP1 conditional knockout (cKO) or wild-type (WT) mice to generate diabetic cKO (cKO/DM) or WT/DM mice for comparison with nondiabetic cKO (cKO/NDM) and WT/NDM mice. Retinal morphology, structure, and function were assessed by immunohistochemistry, optical coherence tomography, and electroretinogram (ERG) after 3 months of diabetes. The synapses between photoreceptors and bipolar cells were examined by confocal microscopy, and synaptic integrity was quantified using the QUANTOS algorithm. Results: We found a thinning of the outer nuclear layer and a decline in the b-wave amplitude in dark- and light-adapted ERG in cKO/DM mice compared to all other groups. In line with these changes, cKO mice showed increased loss of synaptic integrity compared to WT mice, regardless of diabetes status. In searching for candidate molecules responsible for the loss of photoreceptor synaptic integrity in diabetic and XBP1-deficient retinas, we found decreased mRNA and protein levels of DLG4/PSD-95 in cKO/DM retina compared to WT/DM. Conclusions: These findings suggest that XBP1 is a crucial regulator in maintaining synaptic integrity and retinal function, possibly through regulation of synaptic scaffold proteins.

Triple Arthrodesis: How to Manage Failures, Malunion, and Nonunion.

Nonunions are managed by general principles that govern other bone healing sites; however, when confounding with malunion, additional attention must be given. Malunited triple arthrodesis requires a thorough understanding of biomechanical and surgical principles for adequate revision surgery. Due to the rigid nature of arthrodesis surgery on a weight-bearing surface, malunited fusions have very low patient tolerance. The lack of joints leads to a block of bone that can be corrected via derotational osteotomies with wedge supplementation. However, even if a rectus foot is achieved, compensatory motion via the ankle joint commonly causes arthritic long-term sequelae.

Updates of Total Ankle Replacement Revision Options: New Generation Total Ankle Replacement Revision Options, Stemmed Implants, Peri-Articular Osteotomies.

Ankle arthritis is a disabling disease pattern resulting in pain and dysfunction ultimately leading to a reduction in quality of life. Unlike more common arthritides of the knee and hip, ankle arthritis is unique in its presentation with an earlier onset of end-stage disease and an etiology, which is most-commonly posttraumatic in nature. Through continued research and design, improvements have continued to be made as newer generation implants are developed. This article discusses the considerations for revision total ankle replacement based on the current revision options and a treatment algorithm developed by the lead author.

Intellectual Property and Royalty Payments Among Foot and Ankle Surgery Fellowship Faculty.

Faculty of the American College of Foot and Ankle Surgeons and American Orthopedic Foot and Ankle Society fellowship programs are uniquely positioned to provide advanced clinical and surgical training to fellows. One aspect of this training may include product design and mentorship through the associated intellectual property (IP) and patent timeline. This study describes the payments received and IP held among foot and ankle surgery fellowship faculty. A review of foot and ankle surgeons with royalties or license payments disclosed on the CMS Open Payments Database from 2014 to 2020 was conducted. Members with payments were then cross-referenced with the US Patent Full-Text Database to identify patents held. Fellowship affiliation, practice location, patent office, number of patents, citations, patent h-index, type of patent, and yearly payment values were recorded. Among the 2801 surgeons, 53 fellowship affiliates and 46 nonaffiliates maintained at least 1 patent and royalty/license payment. A total of 576 patents and 19,191 citations were assessed. The median number of patents and citations held by fellowship faculty was 3 and 60, respectively, while the median total payment value reached $165,197.09. Fixation devices comprised most of the patents and citations. Payment value positively correlated with number of patents held (p = .01), citations (p = .007), and patent h-index (p = .01) among fellowship-affiliated surgeons. Foot and ankle surgery fellowship faculty payments for IP are associated with the number and citability of patents held. While a small proportion of faculty were paid for intellectual property, the number of patents held and citations was comparable to other specialties.

A Study of Tibial Cyst Formation in Modular Stemmed Total Ankle Arthroplasty: Exploring a Possible Relationship to Smooth and Porous Coating on the Stem Segments.

Vertical fixation through stemmed components has been a successful strategy in total ankle arthroplasty. Research in hip replacement surgery has demonstrated increased rates of stress shielding, aseptic loosening, thigh pain, and cystic formation around stemmed femoral implants extensively coated with porous surfaces. While some ankle prostheses have integrated porous coating technology with stemmed tibial implants, there is little to no research investigating the potential negative effects of bone bonding to the tibial stems and possible impact on tibial cyst formation. We performed a retrospective cohort study comparing the incidence of periprosthetic tibial cyst formation in smooth versus fully porous-coated stemmed tibial implants after undergoing total ankle implant arthroplasty. Radiographs were compared for postoperative rates of tibial cyst formation and bone bonding to the tibial stems. Relative risk for reoperation between the smooth and porous-coated implants was investigated. The smooth-stem group showed no incidence of tibial cyst formation nor signs of significant bone bonding to the tibial stems; however, the follow-up matched porous-coated group showed a rate of 63% of cystic formation with associated evidence of bone bonding on final radiographic follow-up (p < .01). Relative risk for reoperation was 0.74. Despite a higher incidence of tibial cyst formation in the stemmed ankle arthroplasty groups with porous coating, reoperation rates were similar. We theorize that the proximal bonding to the porous stem surface could impact the distal stems and result in the observed increase in cyst formation.

Meta-Analysis on Associations of Timing of Maternal Smoking Cessation Before and During Pregnancy With Childhood Overweight and Obesity.

INTRODUCTION: There is a lack of comprehensive review on associations of maternal smoking cessation (versus nonsmokers) with childhood overweight and obesity. AIMS AND METHODS: We conducted a systematic review and meta-analysis of existing evidence in this field. Within PubMed, EMBASE, and CENTRAL databases, we identified and screened 1147 abstracts. We reviewed full-texts and extracted related information from 10 eligible articles. We pooled odds ratios for overweight/obesity and mean differences in BMI z-scores by maternal smoking status around pregnancy. RESULTS: Among 10 eligible studies, 71 393 children were included from ages 2 to 18 years. Compared to children of nonsmokers, the pooled unadjusted odds ratio (OR) for overweight was 1.36 (95% Confidence Interval CI: 1.14, 1.62) in children of quitters and 1.44 (1.27, 1.64) in children of continued smokers. The pooled unadjusted OR for obesity was 1.65 (1.17, 2.32) in children of quitters and 1.94 (1.38, 2.73) in children of continued smokers. The pooled unadjusted mean difference in BMI z-score was 0.51 (0.41, 0.61) in children of quitters and 0.64 (0.58, 0.70) in children of continued smokers. The pooled unadjusted OR for overweight in children of mothers quitting before pregnancy was 1.46 (1.15, 1.85), during the first trimester was 1.52 (1.27, 1.82), and during pregnancy (mixed timing, mostly first trimester) was 0.97 (0.79, 1.20). CONCLUSION: The risk of offspring overweight and obesity was moderately higher for quitters during pregnancy compared to nonsmokers, although it might not be as high as continued smokers. IMPLICATIONS: Maternal smoking during pregnancy is an established risk factor of childhood overweight and obesity. Based on our systematic review, intervention to help mothers quit smoking has the potential to reduce the risk of childhood overweight and obesity in offspring related to prenatal tobacco exposure. Quitting before pregnancy is ideal, but quitting in early pregnancy is still helpful for reducing risk.

Cellular stress signaling and the unfolded protein response in retinal degeneration: mechanisms and therapeutic implications.

BACKGROUND: The retina, as part of the central nervous system (CNS) with limited capacity for self-reparation and regeneration in mammals, is under cumulative environmental stress due to high-energy demands and rapid protein turnover. These stressors disrupt the cellular protein and metabolic homeostasis, which, if not alleviated, can lead to dysfunction and cell death of retinal neurons. One primary cellular stress response is the highly conserved unfolded protein response (UPR). The UPR acts through three main signaling pathways in an attempt to restore the protein homeostasis in the endoplasmic reticulum (ER) by various means, including but not limited to, reducing protein translation, increasing protein-folding capacity, and promoting misfolded protein degradation. Moreover, recent work has identified a novel function of the UPR in regulation of cellular metabolism and mitochondrial function, disturbance of which contributes to neuronal degeneration and dysfunction. The role of the UPR in retinal neurons during aging and under disease conditions in age-related macular degeneration (AMD), retinitis pigmentosa (RP), glaucoma, and diabetic retinopathy (DR) has been explored over the past two decades. Each of the disease conditions and their corresponding animal models provide distinct challenges and unique opportunities to gain a better understanding of the role of the UPR in the maintenance of retinal health and function. METHOD: We performed an extensive literature search on PubMed and Google Scholar using the following keywords: unfolded protein response, metabolism, ER stress, retinal degeneration, aging, age-related macular degeneration, retinitis pigmentosa, glaucoma, diabetic retinopathy. RESULTS AND CONCLUSION: We summarize recent advances in understanding cellular stress response, in particular the UPR, in retinal diseases, highlighting the potential roles of UPR pathways in regulation of cellular metabolism and mitochondrial function in retinal neurons. Further, we provide perspective on the promise and challenges for targeting the UPR pathways as a new therapeutic approach in age- and disease-related retinal degeneration.

The N-terminal domain of uracil-DNA glycosylase: Roles for disordered regions.

The presence of uracil in DNA calls for rapid removal facilitated by the uracil-DNA glycosylase superfamily of enzymes, which initiates the base excision repair (BER) pathway. In humans, uracil excision is accomplished primarily by the human uracil-DNA glycosylase (hUNG) enzymes. In addition to BER, hUNG enzymes play a key role in somatic hypermutation to generate antibody diversity. hUNG has several isoforms, with hUNG1 and hUNG2 being the two major isoforms. Both isoforms contain disordered N-terminal domains, which are responsible for a wide range of functions, with minimal direct impact on catalytic efficiency. Subcellular localization of hUNG enzymes is directed by differing N-terminal sequences, with hUNG1 dedicated to mitochondria and hUNG2 dedicated to the nucleus. An alternative isoform of hUNG1 has also been identified to localize to the nucleus in mouse and human cell models. Furthermore, hUNG2 has been observed at replication forks performing both pre- and post-replicative uracil excision to maintain genomic integrity. Replication protein A (RPA) and proliferating cell nuclear antigen (PCNA) are responsible for recruitment to replication forks via protein-protein interactions with the N-terminus of hUNG2. These interactions, along with protein degradation, are regulated by various post-translational modifications within the N-terminal tail, which are primarily cell-cycle dependent. Finally, translocation on DNA is also mediated by interactions between the N-terminus and DNA, which is enhanced under molecular crowding conditions by preventing diffusion events and compacting tail residues. This review summarizes recent research supporting the emerging roles of the N-terminal domain of hUNG.

Reducing fetal origins of childhood obesity through maternal smoking cessation during pregnancy: an intervention study.

Rapid infant weight gain predicts childhood obesity. We aimed to estimate effect size and identify critical timing for intervention-assisted smoking cessation during pregnancy to impact infant weight gain. We followed 25 mother-infant dyads in the UB Pregnancy and Smoking Cessation Study (Buffalo, NY, USA). Maternal smoking status was biochemically verified and monitored through pregnancy. Birth weight and length were extracted from birth records. Research staff measured infant weight and length at 2 weeks and monthly from 1 to 12 months of age. Mixed models were used to fit infant BMI-for-age z-score (ZBMI) trajectories. We found infants of quitters had lower ZBMI gain from birth to 12 months (mean ± SD, 1.13 ± 1.16) than infants of persistent smokers (2.34 ± 1.40; p = 0.035), with Cohen's d effect size being large (0.96). The infant ZBMI gain from birth to 12 months was low (<0.47) if smoking cessation was initiated between 15 and 27 weeks of pregnancy, but started to increase if quitting at 28 weeks (0.65) and accelerated with time (e.g., 3.16 if quitting at 36 weeks). We concluded maternal smoking cessation during pregnancy may reduce fetal origins of obesity through reducing infant weight gain, especially if quitting smoking by 27 weeks of pregnancy.

Impact of Violence and Relationship Abuse on Grades of American Indian/Alaska Native Undergraduate College Students.

Violence and relationship abuse are pervasive public health problems that have a range of negative effects, with exceptionally high prevalence among ethno-racial minority youth. This study assesses the prevalence of these types of violence among American Indian/Alaska Native (AI/AN) students and examines the impact of victimization on academic performance of AI/AN and non-AI/AN student populations using self-reported college health survey data. Results show that students who identified fully or partially as AI/AN reported markedly higher rates of all types of violence/abuse than did other students, and students who had experienced violence/abuse had lower grade point averages (GPAs) compared with those who had not. Recommendations for future research and direct practice with AI/AN students are discussed.