Circular RNA PDK1 targets miR-4731-5p to enhance TNXB expression in ligamentum flavum hypertrophy.

Hypertrophic ligamentum flavum (LF) is a main factor responsible for lumbar spinal stenosis (LSS); however, the exact mechanisms of the pathogenesis of these processes remain unknown. This study aimed to elucidate whether circular RNAs and microRNAs regulate the pathogenesis of LF and LSS, especially focusing on circPDK1 (hsa_circ_0057105), a circRNA targeting pyruvate dehydrogenase kinase 1 and differentially expressed in LF tissues between lumbar disk herniation and LSS patients. The circPDK1/miR-4731 and miR-4731/TNXB (Tenascin XB) interactions were predicted and validated by luciferase reporter assay. Colony formation, wound-healing, and MTT assays were used for estimating cell proliferation and migration. Protein expression levels were evaluated using Western blotting. TNXB expression was verified using immunohistochemistry (IHC). Overexpressing circPDK1 promoted the proliferation, migration, and expression of fibrosis-related protein (alpha smooth muscle actin (α-SMA), lysyl oxidase like 2 (LOXL2), Collagen I, matrix metalloproteinase-2 (MMP-2) and TNXB) in LF whereas miR-4731-5p showed opposite effects. The expression of TNXB was promoted by circPDK1; contrary results were observed with miR-4731-5p. Co-overexpression of miR-4731-5p partially reversed the proliferative and fibrosis-prompting effects of circPDK1 or TNXB. The circPDK1-miR-4731-TNXB pathway may be proposed as a regulatory axis in LF hypertrophy, which might shed light on in-depth research of LSS, as well as providing a novel therapeutic target for LF hypertrophy-induced LSS.

Dual-camera compressive hyperspectral imaging based on deep image prior and a guided filter.

Coded aperture snapshot spectral imaging (CASSI) aims to capture the high-dimensional (usually 3D) data cube using a 2D sensor in a single snapshot. Due to the ill-posed snapshot, the reconstruction results are not ideal. One feasible solution is to utilize additional information such as the panchromatic measurement in CASSI. In this paper, we propose a dual-camera hyperspectral reconstruction method based on the deep image prior (DIP) and a guided filter. In particular, the panchromatic measurements are used to estimate spatial detail, and spectral details are provided using CASSI measurements. These measurements are used as a priori learning by the self-supervised network. Using iteration combined with DIP, the hyperspectral reconstruction is continuously updated iteratively. Finally, the panchromatic measurement is used as the guidance image, and the reconstruction result is optimized by guide filtering. A large number of experimental results demonstrate that our method without training data can reconstruct spectral data with both high spectral accuracy and spatial resolution.

Incidence and prevalence of psoriatic arthritis in patients with psoriasis stratified by psoriasis disease severity: Retrospective analysis of an electronic health records database in the United States.

BACKGROUND: Among patients in the United States with psoriasis (PsO), limited data exist on the incidence and prevalence of psoriatic arthritis (PsA) based on disease severity. OBJECTIVE: To assess the incidence, prevalence, and predictors of PsA among patients with PsO stratified by PsO severity using treatment type. METHODS: Incidence of PsA per 100 PsO patient-years (PY) and prevalence were assessed using the Optum electronic health records database. Incidence was assessed from PsO diagnosis and 1 year after PsO diagnosis overall and stratified by mutually exclusive treatment classes as a severity surrogate. RESULTS: The overall incidence of PsA was 2.9 (95% CI, 2.9-3.0) events per 100 PY. The incidence (95% CI) by severity surrogate was 2.1 (2.1-2.1), 9.9 (9.5-10.4), and 17.6 (16.9-18.3) events per 100 PY for patients with mild, moderate, and severe PsO as determined by receiving nonsystemics, nonbiologic systemic therapy, and biologics, respectively. When excluding patients diagnosed with PsA 1 year after PsO diagnosis, overall incidence was lower (1.7 [95% CI, 1.6-1.7] events per 100 PY), with similar trends for treatment-severity surrogates. LIMITATIONS: Results may not be generalizable to a wider population. CONCLUSION: The risk of developing PsA increased with disease severity and was highest in patients with the most severe PsO.

Polydopamine-coated UiO-66 nanoparticles loaded with perfluorotributylamine/tirapazamine for hypoxia-activated osteosarcoma therapy.

BACKGROUND: Hypoxia is a characteristic of solid tumors that can lead to tumor angiogenesis and early metastasis, and addressing hypoxia presents tremendous challenges. In this work, a nanomedicine based on oxygen-absorbing perfluorotributylamine (PFA) and the bioreductive prodrug tirapazamine (TPZ) was prepared by using a polydopamine (PDA)-coated UiO-66 metal organic framework (MOF) as the drug carrier. RESULTS: The results showed that TPZ/PFA@UiO-66@PDA nanoparticles significantly enhanced hypoxia, induced cell apoptosis in vitro through the oxygen-dependent HIF-1α pathway and decreased oxygen levels in vivo after intratumoral injection. In addition, our study demonstrated that TPZ/PFA@UiO-66@PDA nanoparticles can accumulate in the tumor region after tail vein injection and effectively inhibit tumor growth when combined with photothermal therapy (PTT). TPZ/PFA@UiO-66@PDA nanoparticles increased HIF-1α expression while did not promote the expression of CD31 in vivo during the experiment. CONCLUSIONS: By using TPZ and PFA and the enhanced permeability and retention effect of nanoparticles, TPZ/PFA@UiO-66@PDA can target tumor tissues, enhance hypoxia in the tumor microenvironment, and activate TPZ. Combined with PTT, the growth of osteosarcoma xenografts can be effectively inhibited.

Laminoplasty with selective fusion at unstable segment versus laminectomy with fusion for multilevel cervical myelopathy: a case-control study.

BACKGROUND: Segmental cervical instability is a risk factor for the progression of osteophytic bone spurs and development of myelopathy, and is treated as a relative contraindication of cervical laminoplasty. The aim of this study was to compare laminoplasty with selective fixation (LPSF) versus laminectomy with fusion (LCF) in patients with multilevel cervical myelopathy accompanied by segmental instability. METHODS: A case-control study was conducted by reviewing data from 63 patients who underwent LPSF (n = 30) or LCF (n = 33). Cervical alignment, range of motion (ROM), neurologic status and axial symptom severity pre-operation, 3-days after operation, and at the final follow-up (minimum 24 months) were measured and compared between groups. RESULTS: Postoperation, patients in the LPSF group lost 31.1 ± 17.3 % of cervical lordosis and 43.2 ± 10.9 % cervical ROM while patients in the LCF group lost 5.7 ± 8.2 % and 67.9 ± 15.5 %, respectively. Both LPSF and LCF groups significantly improved neurologic status and axial symptom severity at the final follow-up with similar between-group results(P > 0.05). Blood loss, operation time, hospital stay, and medical cost in the LPSF group were significantly less than in the LCF group(P < 0.05). CONCLUSIONS: In 2 years of clinical observation, LPSF was effective in maintaining the stability of the cervical spine with less sacrifice of mobility and surgical trauma for multilevel myelopathy with segmental instability compared to LCF.

Pain and Fatigue in Patients With Ankylosing Spondylitis Treated With Tumor Necrosis Factor Inhibitors: Multinational Real-World Findings.

BACKGROUND/OBJECTIVE: Patients with ankylosing spondylitis (AS) experience symptoms and comorbidities that impact their health-related quality of life (HRQoL) and ability to work. This real-world, global survey was conducted among AS patients receiving tumor necrosis factor inhibitors (TNFis) to evaluate both the frequency and severity of persistent symptoms, and the impact of pain and fatigue on HRQoL, employment status, and work activity. METHODS: Patients with AS and their treating physicians from 13 countries across 5 continents completed questionnaires capturing demographics, patient symptoms, current disease status, HRQoL, current therapy, employment status, and Work Productivity and Activity Impairment. RESULTS: Seven hundred five patients who had been receiving a TNFi for 3 months or more and completed both Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) pain and fatigue domains were included in the analysis; of these, 37.6% reported high BASDAI pain scores and 41.3% high BASDAI fatigue scores. Medical Outcomes Study-Short Form, 36-item version 2 domain, 5-dimensional EuroQoL Questionnaire, and 5-dimensional EuroQoL visual analog scale scores were significantly lower (p < 0.0001), and Work Productivity and Activity Impairment scores significantly higher (p < 0.0001), in patients with high levels of pain or fatigue than low levels. CONCLUSIONS: Globally, levels of pain and fatigue remained high in AS patients receiving TNFi treatment, which were significantly associated with reduced HRQoL and work productivity. Such persistent symptoms in usual care suggest a substantial unmet need in AS pharmacologic and nonpharmacologic therapeutic pathways.

Incidence of Psoriatic Arthritis in Patients with Skin Psoriasis and Associated Risk Factors: A Retrospective Population-based Cohort Study in Swedish Routine Clinical Care.

The incidence of psoriatic arthritis in patients with psoriasis is unclear; existing estimates differ by a factor of ten. Complete population-level data is needed to provide accurate estimates with high confidence. A total of 123,814 adults with psoriasis, free from pre-existing psoriatic arthritis, were identified in population-based data from secondary care in Sweden during 2007 to 2017. Incidence was calculated as the number of psoriatic arthritis diagnosis events per 100 patient-years. Time to diagnosis was assessed using cumulative incidence and Cox proportional hazards models to identify risk factors. Incidence of psoriatic arthritis in patients with psoriasis was 1.69 per 100 patient-years (95% confidence interval 1.65-1.72) overall, and 1.48, 3.00, and 5.49 per 100 patient-years in patients with mild, moderate and severe psoriasis, respectively. Risk of psoriatic arthritis was 3.2 times higher amongst patients with severe psoriasis compared with mild disease. Dermatologists should regularly assess risk factors for psoriatic arthritis in clinical practice in order to improve the detection of psoriatic arthritis.

Wnt5a/FZD4 Mediates the Mechanical Stretch-Induced Osteogenic Differentiation of Bone Mesenchymal Stem Cells.

BACKGROUND/AIMS: Mechanical stimulation and WNT signalling have essential roles in regulating the osteogenic differentiation of bone marrow stromal cells (BMSCs) and bone formation. However, little is known regarding the regulation of WNT signalling molecule expression and therefore the osteogenic differentiation of BMSCs during osteogenesis. METHODS: Microarrays of BMSCs from elderly individuals or patients with osteoporosis (GSE35959) from the GEO database were analysed using GeneSight-Lite 4.1.6 (BioDiscovery) and C2 curated gene sets downloaded from Molecular Signatures Database (MSigDB). Realtime PCR and western blotting were used to measure the expression of the indicated genes. ALP and Alizarin red staining were used to evaluate the osteogenesis of BMSCs. RESULTS: In this study, we investigated whether mechanical loading directly regulates the expression of WNT signalling molecules and examined the role of WNT signalling in mechanical loading-triggered osteogenic differentiation and bone formation. We first studied the microarrays of samples from patients with osteoporosis and found downregulation of the GPCR ligand binding gene set in the BMSCs of patients with osteoporosis. Then, we demonstrated that mechanical stimuli can regulate osteogenesis and bone formation both in vivo and in vitro. FZD4 was upregulated during cyclic mechanical stretch (CMS)-induced osteogenic differentiation, and the JNK signalling pathway was activated. FZD4 knockdown inhibited the mechanical stimuli-induced osteogenesis and JNK activity. More importantly, we found an activating effect of WNT5A and FZD4 that regulated bone formation in response to hindlimb unloading in mice, and pretreatment with WNT5A or activation of the expression of FZD4 partly rescued the osteoporosis caused by mechanical unloading. CONCLUSIONS: Our results demonstrate, for the first time, that mechanical stimulation alters the expression of genes involved in the osteogenic differentiation of BMSCs via the direct regulation of FZD4 and that therapeutic WNT5A and FZD saRNA may be an efficient strategy for enhancing bone formation under mechanical stimulation.

Systemic Medication Associations with Presumed Advanced or Uncontrolled Primary Open-Angle Glaucoma.

PURPOSE: To identify associations between systemic medications and primary open-angle glaucoma (POAG) requiring a procedure using United States insurance claims data in a hypothesis-generating study. DESIGN: Database study. PARTICIPANTS: In total, 6130 POAG cases (defined as patients with POAG undergoing a glaucoma procedure) were matched to 30 650 controls (defined as patients undergoing cataract surgery but without a coded glaucoma diagnosis, procedure, or medication) by age, gender, and region of residence. METHODS: Participant prescription drug use was calculated for the 5-year period before the glaucoma procedure or cataract surgery. Separately for individual generic drugs and drug classes, logistic regression was used to assess the association with POAG status. This was done across all generic drugs and drug classes that were prescribed in at least 1% of cases and controls. Analyses were adjusted for age, sex, region of residence, employment status, insurance plan type, and the total number of drugs prescribed. MAIN OUTCOME MEASURES: Odds ratio (OR) and 95% confidence intervals (CIs) for the association between each drug or drug class and POAG. RESULTS: The median age of participants was 72 years, and 52% were women. We tested for associations of POAG with 423 drug classes and 1763 generic drugs, resulting in a total of 2186 statistical tests and a Bonferroni-adjusted significance threshold of P < 2.3 × 10-5. Selective serotonin reuptake inhibitors (SSRIs) were strongly associated with a reduced risk of POAG (OR, 0.70; 95% CI, 0.64-0.76; P = 1.0 × 10-15); the most significant drug in this class was citalopram (OR, 0.66; 95% CI, 0.57-0.77; P = 1.2 × 10-7). Calcium channel blockers were strongly associated with an increased risk of POAG (OR, 1.26; 95% CI, 1.18-1.35; P = 1.8 × 10-11); the most significant drug in this class was amlodipine (OR, 1.27; 95% CI, 1.18-1.37; P = 5.9 × 10-10). CONCLUSIONS: We present data documenting potential associations of SSRIs and calcium channel blockers with POAG requiring a procedure. Further research may be indicated to better evaluate any associates of serotonin metabolism or calcium channels in glaucoma, or establish whether the associations are due to variations in the patterns for prescribing these drugs.

Prevalence and clinical characteristics of chronic spontaneous urticaria in pediatric patients.

BACKGROUND: Data on the prevalence and disease management of chronic urticaria (CU) and chronic spontaneous urticaria (CSU) in the pediatric population are scarce. This study assessed the prevalence of CU and CSU, and disease management among pediatric patients (0-17 years). METHODS: A physician-based online survey was conducted in 5 European countries (United Kingdom, Germany, Italy, France, and Spain) assessing the annual diagnosed prevalence, disease characteristics, and treatment patterns in the target population. Results are based on physician responses and analyzed using descriptive statistics. Prevalence estimates were calculated based on the number of CU/CSU pediatric patients diagnosed, seen, and treated by the respondents and extrapolated to the total pediatric population from each country. RESULTS: Across 5 European countries, the one-year diagnosed prevalence of CU and CSU in pediatric patients was 1.38% (95% CI, 0.94-1.86) and 0.75% (95% CI, 0.44-1.08), respectively. Angioedema was reported in 6%-14% of patients. A large proportion of CSU pediatric patients (40%-60%) were treated with H1-antihistamines at approved dose and 16%-51% received H1-antihistamines at higher doses. Approximately 1/3 of pediatric CSU patients remained uncontrolled with H1-antihistamines at approved/higher doses. Other prescribed treatments were oral corticosteroids (10%-28%) and topical creams (15%-26%). CONCLUSIONS: This study revealed a prevalence of CSU among pediatric population comparable to adults and also suggested an unmet need for approved treatments for inadequately controlled pediatric CSU patients. It is truly of concern that harmful (oral steroids) or insufficient (topical creams) treatments were frequently used despite better and guideline-recommended alternatives.

Ankylosing spondylitis causes high burden to patients and the healthcare system: results from a German claims database analysis.

To compare healthcare resource utilization and costs between ankylosing spondylitis (AS) patients and a matched sample from the general population without AS covered by the German Statutory Health Insurance (SHI) system, a non-interventional retrospectively matched cohort analysis was conducted using anonymized SHI claims data. Data from January 1st, 2011 through December 31st, 2014 were analyzed. Individuals with a coded diagnosis of AS during the enrollment period comprising the full year of 2013 were directly matched (1:5) to individuals without AS diagnosis in the whole study period by age, gender, hospitalizations, and comorbidities. All-cause healthcare resource utilization and direct costs were analyzed for the year 2013. Statistical tests were applied to compare the differences between the two sampled populations. In 2013, 10,208 AS patients were identified and matched to a sample of 51,040 patients without AS from the general population. Healthcare resource utilization was significantly higher in all healthcare sectors (inpatient, outpatient, pharmaceuticals, remedies, devices and aids, and sick leave) in the AS cohort. Mean all-cause healthcare costs per patient were about €2475 higher in the AS cohort compared to the general population. Most important cost drivers were hospitalizations and pharmaceuticals in terms of bDMARDs prescribed in 10% of the patients. Real-world data from this German claims database analysis showed that AS is associated with a substantial incremental economic burden to the healthcare system.

Incidence rates of comorbidities among patients with psoriasis in the United States.

Psoriasis is associated with a substantial burden of comorbidities; however, incidence rates (IRs) of these comorbidities following psoriasis diagnosis are not well characterized. Using administrative claims data from the Truven Health Analytics MarketScan Commercial and Medicare Supplemental Databases between January 1, 2002 and September 30, 2015, we compared the incidence of newly diagnosed comorbidities among patients with psoriasis versus demographically matched (birth year, gender, and geographic region) control patients without psoriasis in the United States. Comorbidities of interest were identified using ICD-9-CM codes. A total of 114,824 matched pairs of patients with psoriasis and control patients were included. IRs of all selected comorbidities were significantly higher among patients with psoriasis compared with controls (P<0.05). The most common newly diagnosed comorbidities in both groups were hyperlipidemia (psoriasis versus control, IR per 1,000 patient-years, 127.5 versus 102.8) and hypertension (94.3 versus 80.6). The greatest differences in IRs between patients with psoriasis and controls were observed for rheumatoid arthritis (9.7 versus 3.1; IR ratio [IRR], 3.15) and psoriatic arthritis (24.0 versus 0.2; IRR, 151.57). In this real-world study, patients with psoriasis were more likely to develop new selected comorbidities after diagnosis compared with demographically matched patients without psoriasis.

Burden of illness and healthcare resource use in United States patients with sporadic inclusion body myositis.

INTRODUCTION: We analyzed the burden of illness of sporadic inclusion body myositis (sIBM) patients and the costs to the healthcare system. METHODS: A retrospective cohort analysis of 333 sIBM patients aged ≥ 50 years was performed using United States (U.S.) claims data. sIBM patients were matched in a 1:5 ratio to randomly selected individuals with ≥1 healthcare encounter within the year of index date. RESULTS: sIBM patients presented with higher rates of disease- and muscle-related conditions, such as myalgia, myositis, muscle weakness, dysphagia, pneumonia, and falls. Use of healthcare resources, including physical therapy, office visits, emergency room (ER) visits, and hospitalizations, was greater in sIBM patients. This was also reflected in significantly higher overall healthcare costs in the sIBM population driven mainly by more all-cause office visits, all-cause ER visits and hospitalizations. CONCLUSIONS: sIBM imposes a substantial burden on U.S. patients in terms of additional healthcare usage and associated costs. Muscle Nerve 56: 861-867, 2017.

Economic burden of comorbidities in psoriasis patients in the United States: results from a retrospective U.S. database.

BACKGROUND: Psoriasis is a multifactorial, inflammatory, skin disease associated with various comorbidities. The cost of those comorbidities is not well characterized. The present study assesses the incremental burden of comorbidities on healthcare resource utilization, direct costs and indirect costs associated with short-term disabilities among patients with psoriasis in the United States. METHODS: A retrospective, U.S. cohort analysis was conducted using a large claims database. Adult psoriasis patients with at least two diagnoses of psoriasis during the years 2010 and 2011 (one psoriasis diagnosis had to happen in the year 2010) and with continuous enrollment of medical and pharmacy benefits in the years 2010 and 2011 were included. Psoriasis patients were categorized and compared according to the presence or absence of pre-selected comorbidities in the year 2010. Adjusted annual direct (costs associated with outpatient, emergency room, and inpatient claims, and outpatient pharmacy claims) and indirect costs (short-term disabilities) was assessed in patients with and without comorbidities using a regression analysis, controlling for age, gender, and psoriasis severity in year 2010. RESULTS: In total, 56,406 patients (mean [SD]) age, 51.6 [14.6] years) were included in the analysis. The most prevalent comorbidities were hypertension (34.3%), hyperlipidemia (33.5%), cardiovascular disease (17.7%), diabetes (14.2%), and psoriatic arthritis (9.9%). Psoriasis patients with comorbidities used more healthcare resources than those without comorbidities. The incidence rate ratio (IRR) (95% CI) for patients with cardiovascular disease was 1.5 (1.4 - 1.5) for outpatient visits, 2.6 (2.4 - 2.8) for hospitalizations, and 2.3 (2.2 - 2.5) for ER visits, showing higher IRRs across all three types of resource use. The mean annual adjusted direct cost differences (i.e., incremental adjusted costs) in psoriasis patients with and without comorbidities were $9914.3, $8386.5, and $8275.1 for psoriatic arthritis, peripheral vascular disease, and cardiovascular disease, respectively. The mean annual incremental adjusted indirect costs of short-term disabilities were $1333, $1195, $994.9, and $996.6 for cerebrovascular disease, obesity, peripheral vascular disease, and depression, respectively. CONCLUSION: The presence of comorbidities was associated with higher healthcare resource utilization and costs among patients with psoriasis.

A carboxy terminal BMP/TGF-ß binding site in secreted phosphoprotein 24 kD independently affects BMP-2 activity.

Secreted phosphoprotein 24 kD (spp24) is a bone matrix protein isolated during attempts to identify osteogenic proteins. It is not osteogenic but performs other important roles in the regulation of bone metabolism, at least in part, by binding to and affecting the activity of members of the BMP/TGF-ß family of cytokines. Spp24 exists in a number of forms that preserve the N-terminus and are truncated at the C-terminus. The hypothesized cytokine binding domain is present within the cystatin domain which is preserved in all of the N-terminal products. In this report, we describe a C-terminal fragment that is distinct from the cystatin domain and which independently binds to BMP-2 and TGF-ß. This fragment inhibited BMP-2 activity in an ectopic bone forming assay. A shorter C-terminal product did not inhibit BMP-2 activity but improved bone quality induced by BMP-2 and produced increased calcium deposition outside of bone. Spp24 has been used to develop several potential therapeutic proteins. These results provide more information on the function of spp24 and provide other materials that can be exploited for clinical interventions.

Secreted phosphoprotein 24 kD (Spp24) inhibits growth of human pancreatic cancer cells caused by BMP-2.

The emerging role of bone morphogenetic proteins (BMPs) in the initiation and progression of multiple cancers has drawn great attention in cancer research. In this study, we report that BMP-2 can promote the proliferation of the pancreatic tumor cell line, PANC-1. Secreted phosphoprotein 24 kD (Spp24), a BMP binding protein, did not affect the proliferation of the cells but promoted the apoptosis of the cells in vitro. In a xeneograft tumor model using PANC-1 cells, BMP-2 dramatically promoted tumor growth, while Spp24 not only abolished the effect of BMP-2, but also dramatically induced tumor shrinking when used alone. Activation of Smad1/5/8 participated in this process as demonstrated by immunohistochemical staining of phosphorylated Smad 1/5/8. We conclude that Spp24 can be developed into a therapeutic agent that could be employed in clinical situations where the inhibition of BMPs and related proteins is advantageous.

Effect of chronic urticaria on US patients: analysis of the National Health and Wellness Survey.

BACKGROUND: Chronic idiopathic (also called spontaneous) urticaria (CIU/CSU) is the most common form of chronic urticaria and has been associated with impairment to health outcomes, although the effect has never been assessed using a nationally representative sample in the United States. OBJECTIVES: To assess the burden of CIU/CSU from the patients' perspective in terms of health related quality of life, impairment to work and nonwork activities, and health care resource use. METHODS: Data were obtained from the US National Health and Wellness Survey. Current use of a prescription for the treatment of chronic hives was used as a proxy for CIU/CSU. Patients with CIU/CSU in the proxy group were matched 1:4 to respondents without chronic hives using survey year, sex, age, and race. Generalized linear models were adjusted for comorbidities, smoking, body mass index, and health insurance status. Outcome measures included the Medical Outcomes Study 12-Item and 36-Item Short Form Health Surveys; self-reported depression, anxiety, and sleep difficulties; the Work Productivity and Activity Impairment questionnaire, and health care resource use. RESULTS: After matching and adjustment for covariates, those currently using a prescription for chronic hives had mental component summary scores 5.7 points lower, physical component summary scores 6.5 points lower, and health utility scores 0.11 points lower than controls, as well as higher adjusted odds of reporting depression, anxiety, and sleep difficulties. Mean adjusted work impairment was approximately double in prescription-treated chronic hives relative to controls, as was frequency of health care visits. CONCLUSION: Chronic hives substantially affects quality of life, nonwork activities, capacity to work, and health care use, providing further evidence of a high burden of CIU/CSU across multiple health outcomes and unmet need for effective treatment.

The effect of bone morphogenetic protein-2 injection at different time points on intervertebral disk degeneration in a rat tail model.

STUDY DESIGN: Prospective in vivo rat tail model of disk degeneration comparing the effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) injection over various time points and grades of degeneration. OBJECTIVE: To evaluate the effect of timing and disk grade on rhBMP-2 injection in a rat tail model of disk degeneration. SUMMARY OF BACKGROUND DATA: rhBMP-2 stimulates the proliferation of intervertebral disk cells and the secretion of extracellular matrix. However, few in vivo studies have demonstrated whether rhBMP-2 also improves disk degeneration and the severity of disk degeneration beyond which disks cannot be recovered by rhBMP-2 treatment. METHODS: Two coccygeal disks of each rodent subject were punctured percutaneously using an 18 G needle. At 4 weeks after the puncture, disks demonstrating induced degeneration were divided into 3 groups. Groups 1, 2, and 3 were treated with 7.5 µg rhBMP-2 or phosphate buffered saline by injection into the disk at 4, 6, and 8 weeks postpuncture, respectively. Plain radiographs and magnetic resonance images (MRIs) were obtained on the day of puncture and every 2 weeks thereafter until sacrifice. At 6 weeks after injection, each group was killed and examined with histologic and immunohistochemical analysis. RESULTS: According to MRI disk grade evaluation of the degenerative disk, rhBMP-2 significantly improved degeneration grade in group 1 at 2 weeks after injection. According to radiographic disk height index, groups 1 and 2 showed a trend toward improvement at 2 weeks after rhBMP-2 injection. Chondrogenic differentiation was noted on immunohistochemical staining of many disks treated with rhBMP-2. CONCLUSIONS: rhBMP-2 injection of degenerated disks at 4 weeks postpuncture induced a transient improvement in disk grade on MRI and stimulated chondrogenic differentiation. These data suggest rhBMP-2 as a potential therapy for degenerative disk disease.

Economic burden associated with extrapyramidal symptoms in a medicaid population with schizophrenia.

No studies have assessed the economic impact of extrapyramidal symptoms due to atypical antipsychotics in schizophrenia. To assess healthcare resource use and medical costs associated with extrapyramidal symptoms in patients with schizophrenia. A retrospective analysis of Marketscan(®) Medicaid Multi-State Database (2004-2009) was conducted. Patients with schizophrenia and newly initiated on an AAP were included. Patients with and without extrapyramidal symptoms were matched using propensity-score matching. Healthcare utilization and costs were assessed in the 12-month follow-up period using logistic and two-part (gamma) regression models. Of 4,621 patients, 583 (12.6 %) had extrapyramidal symptoms. Patients with extrapyramidal symptoms had significantly more schizophrenia-related and all-cause hospitalizations and schizophrenia-related emergency room visits, as well as significantly higher schizophrenia-specific and all-cause total healthcare, inpatient, and prescription drug costs compared to patients without extrapyramidal symptoms. Extrapyramidal symptoms in patients with schizophrenia is associated with increased healthcare resource utilization and higher medical costs.

Hypoxia-Preconditioned BMSC-Derived Exosomes Induce Mitophagy via the BNIP3-ANAX2 Axis to Alleviate Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is a chronic degenerative disease involving the aging and loss of proliferative capacity of nucleus pulposus cells (NPCs), processes heavily dependent on mitochondrial dynamics and autophagic flux. This study finds that the absence of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) is associated with senescence-related NPC degeneration, disrupting mitochondrial quality control. Bone marrow mesenchymal stem cells (BMSCs) have multidirectional differentiation potential and produce extracellular vesicles containing cellular activators. Therefore, in this study, BMSCs are induced under hypoxic stimulation to deliver BNIP3-rich extracellular vesicles to NPCs, thereby alleviating aging-associated mitochondrial autophagic flux, promoting damaged mitochondrial clearance, and restoring mitochondrial quality control. Mechanistically, BNIP3 is shown to interact with the membrane-bound protein annexin A2 (ANXA2), enabling the liberation of the transcription factor EB (TFEB) from the ANXA2-TFEB complex, promoting TFEB nuclear translocation, and regulating autophagy and lysosomal gene activation. Furthermore, a rat model of IVDD is established and verified the in vivo efficacy of the exosomes in repairing disc injuries, delaying NPC aging, and promoting extracellular matrix (ECM) synthesis. In summary, hypoxia-induced BMSC exosomes deliver BNIP3-rich vesicles to alleviate disc degeneration by activating the mitochondrial BNIP3/ANXA2/TFEB axis, providing a new target for IVDD treatment.