Lifestyles and health-related quality of life in Chinese people: a national family study.

BACKGROUND: There were few studies that investigated health-related quality of life (HRQoL) of the general population in China, and many of them reported limitations in sampling. OBJECTIVE: To investigate the relationship between lifestyles and HRQoL in the Chinese population in both individual and family levels. METHOD: Online questionnaires were distributed across China to collect demographic information and participants' HRQoL using EuroQoL 5 Dimension scales. The EuroQoL Group's 5 Dimension scale (EQ-5D) index and EuroQoL Group's visual analog scale (EQ VAS) score were calculated to evaluate the HRQoL. RESULTS: A total of 1305 valid questionnaires were included. Higher HRQoL was found in people with intend to lower oil intake, intend to lower salt intake, intend to lower sugar intake, balanced diet, moderate sports every week, a sport hobby and joining a fitness organization (all p<.05). HRQoL was higher among male (female as reference), healthy weight (unhealthy weight as reference) (both p<.05). Negative correlation was found between HRQoL and clinical medical history and drinking history. Small families (1-2 persons, 83.19 ± 20.14) had poorer HRQoL (EQ VAS score) than big families (≥3 persons, 85.00 ± 17.96, p <.05). CONCLUSION: In China, people with healthy dietary habits, regular sports habits, healthy weight and male groups tended to have better HRQoL. Clinical medical history and drinking history were negatively related to HRQoL. Small families tend to have poorer HRQoL than big families. The finding implicated influence of the number of family members on people's perception of health and provided scientific evidence for the current policies to encourage birth in China. For a better HRQoL, we suggest people live in big families and take measures to lower salt/sugar/oil intake and exercise regularly in daily life.

Status of medication literacy and its related factors among undergraduate students in Shanxi Province, China: A cross-sectional study.

WHAT IS KNOWN AND OBJECTIVE: Medication safety problem has always been the focus of healthcare providers and public health community scholars. As the backbone of the future society, the mastery of college students' knowledge to use medicine will directly affect the level of medication literacy (ML) of the public in the future. The purpose of this study was to investigate the current ML of college students in Shanxi Province and to identify its related factors. METHODS: A cluster random sampling method was utilized to select 800 college students from 10 universities in Shanxi province as participants from 21 March to 10 April 2020. After quality control, 763 valid questionnaires were collected (effective rate 95.4%). This study applied the ML scale adapted from the 14-item health literacy scale (HLS-14) to estimate ML, which contains functional ML, communicative ML and critical ML dimensions to estimate the ML situation. Then, we used structural equation modelling (SEM) to test the hypothesized relationship among three dimensions of ML, self-evaluated health status and safety medication science popularization activities on campus. RESULTS AND DISCUSSION: The results showed that the reliability and validity of the ML scale were good. The average score of ML level of college students in Shanxi Province was 44 points, and the interquartile range was 40-48 points (full score is 65 points). The proportion of high ML level was estimated at as low as 26.7%. 73.1% participants had an average level, and only 1 participant (0.1%) had a low level of ML. Univariate analysis showed that the ML level was significantly influenced by gender, universities, field of study, academic performance and ethnic group (p < 0.05). SEM showed that functional ML (λ = 0.01) and communicative ML (λ = 0.75) had a direct positive association with critical ML. Meanwhile, the model also had a mediating effect. Functional ML had an indirect positive association with critical ML through the mediating effect of communicative ML (λ = 0.11). In addition, both self-evaluated health status and safety medication science popularization activities on campus had an indirect positive association with critical ML through the mediating effect of functional ML and communicative ML. WHAT IS NEW AND CONCLUSION: The study revealed that the ML of most college students in Shanxi Province was at the average level. Among them, medical college student (including pharmacy, nursing, public health, preventive medicine, basic medicine and clinical medicine students), the Han nationality students (the students of China's majority ethnic group), students of good self-evaluated health status, and students who were more exposed to safety medication science popularization activities had a relatively higher ML level. Moreover, it highlighted the importance of self-evaluated health status and safety medication science popularization activities on campus to ML.

A novel spectral multivariate calibration approach based on a multiple fitting method.

This paper introduces a novel multivariate regression approach based on a multiple fitting algorithm that combines fitting functions to accordingly configure different regression models for the quantitative analysis of spectra data. The novel regression method employs multivariate fitting functions to characterize the potential functional relationship of spectral information and sample information with the corresponding attributes, and uses single fitting function elements as the independent variables for biased parameters to determine the amplitude of each fitting function. The peak width of the different fitting functions and the biased parameters are optimized by a simulated annealing algorithm. After parameter optimization, the fitting functions are superposed together to form a functional super surface, and a multiple fitting regression model is then used to characterize any functional relationship among the spectral variable information, sample information, and the corresponding analyte information. In this paper, a common fitting function, namely the Gaussian function, is used to create multiple fitting regression models. The simulated dataset and two real near infrared spectral datasets were used to validate the multiple fitting regression model. The results are compared to those obtained using partial least squares regression and least squares support vector regression. It is shown that the proposed multiple fitting regression algorithm achieved an accuracy comparable to the two conventional methods. Therefore, the multiple fitting regression is demonstrated to be a useful tool for spectra multivariate regression analysis and may also be suitable for linear and nonlinear multivariate calibration.

Therapeutic plasma exchange and immunosuppressive therapy in a patient with anti-GAD antibody-related epilepsy: quantification of the antibody response.

Antibodies to glutamic acid decarboxylase (GAD) have been associated with a host of neurological disorders including stiff person syndrome, cerebellar ataxia, limbic encephalitis, and epilepsy. Whether anti-GAD antibodies have an etiological role in these neurological disorders or simply serve as disease markers is unclear. Here, we report a case of a patient with recurrent seizures, poorly responsive to conventional treatment, associated with anti-GAD antibodies. The patient was experiencing near daily seizures at the time of presentation and had marked improvement while receiving immunosuppressive therapy and therapeutic plasma exchange (TPE). We go on to show that the patient had a substantial reduction of her GAD autoantibody burden following this therapy. Using immunostaining, we further demonstrate a progressive loss of GAD reactivity in the patient's sera to neurons and GAD-expressing HELA cells with successive TPEs. Hence, these data support the concept of an immune-mediated pathogenic component to these autoantibody-associated neurological syndromes.

ADAMTS-7 forms a positive feedback loop with TNF-α in the pathogenesis of osteoarthritis.

OBJECTIVE: To examine the expression of ADAMTS-7 during the progression of osteoarthritis (OA), defining its role in the pathogenesis of OA, and elucidating the molecular events involved. METHODS: ADAMTS-7 expression in cartilage of a rat OA model was assayed using immunohistochemistry. Cartilage-specific ADAMTS-7 transgenic mice and ADAMTS-7 small interfering (si)RNA knockdown mice were generated and used to analyse OA progression in both spontaneous and surgically induced OA models. Cartilage degradation and OA was evaluated using Safranin-O staining, immunohistochemistry, ELISA and western blotting. In addition, mRNA expression of tumour necrosis factor (TNF)-α and metalloproteinases known to be involved in cartilage degeneration in OA was analysed. Furthermore, the transactivation of ADAMTS-7 by TNF-α and its downstream NF-κB signalling was measured using reporter gene assay. RESULTS: ADAMTS-7 expression was elevated during disease progression in the surgically induced rat OA model. Targeted overexpression of ADAMTS-7 in chondrocytes led to chondrodysplasia characterised by short-limbed dwarfism and a delay in endochondral ossification in 'young mice' and a spontaneous OA-like phenotype in 'aged' mice. In addition, overexpression of ADAMTS-7 led to exaggerated breakdown of cartilage and accelerated OA progression, while knockdown of ADAMTS-7 attenuated degradation of cartilage matrix and protected against OA development, in surgically induced OA models. ADAMTS-7 upregulated TNF-α and metalloproteinases associated with OA; in addition, TNF-α induced ADAMTS-7 through NF-κB signalling. CONCLUSIONS: ADAMTS-7 and TNF-α form a positive feedback loop in the regulation of cartilage degradation and OA progression, making them potential molecular targets for prevention and treatment of joint degenerative diseases, including OA.

Risk Factors, Antithrombotic Management, and Long-term Outcomes of Patients Undergoing Endovascular Treatment of Unruptured Intracranial Aneurysms.

Background Patients receiving endovascular treatment for unruptured intracranial aneurysms (UIA) face varying risks and benefits with antithrombotic management. This study aimed to evaluate the perioperative and long-term effects of antithrombotic strategies, identify the populations that would benefit, and explore the predictive factors affecting the long-term outcomes. Methods UIA patients undergoing endovascular treatment including stent-assisted coiling (SAC) or flow diversion (FD) between June 2019 and June 2022 were enrolled. We compared perioperative and long-term complications between tirofiban and dual antiplatelet therapy groups. Optimal candidates for each antithrombotic treatment were identified using multivariate logistic regression. Nomograms were developed to determine the significant predictors for thromboembolic complications during follow-up. Results Among 181 propensity-score (PS) matched pairs, tirofiban group showed a trend towards a lower rate of thromboembolic complications than DAPT group without elevating major bleeding risk in either period. Homocysteine (Hcy) level ≥ 10 µmol/L was a significant independent factor associated with thromboembolic complication in both periods. Subgroup analysis highlighted that in patients with high Hcy levels, tirofiban and sustained antiplatelet treatment for ≥ 12 months were protective factors, while a history of stroke was an independent risk factor for thromboembolic events in follow-up. Four variables were selected to construct a prognostic nomogram, history of hypertension, prior stroke, Hcy level, and the duration of antiplatelet therapy. Conclusion Perioperative low-dose tirofiban and extended antiplatelet therapy demonstrated a favorable trend in long-term outcomes for UIA patients with preoperative Hcy levels≥10µmol/L undergoing endovascular treatment. The prognostic model offers reliable risk prediction and guides antithrombotic strategy decisions.

GEP constitutes a negative feedback loop with MyoD and acts as a novel mediator in controlling skeletal muscle differentiation.

Granulin-epithelin precursor (GEP) is an autocrine growth factor that has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation. Here we report that GEP was expressed in skeletal muscle tissue and its level was differentially altered in the course of C2C12 myoblast fusion. The GEP expression during myoblast fusion was a consequence of MyoD transcription factor binding to several E-box (CANNTG) sequences in the 5'-flanking regulatory region of GEP gene, followed by transcription. Recombinant GEP potently inhibited myotube formation from C2C12 myoblasts whereas the knockdown of endogenous of GEP via a siRNA approach accelerated the fusion of myoblasts to myotubes. Interestingly, the muscle fibers of GEP knockdown mice were larger in number but noticeably smaller in size when compared to the wild-type. Mechanistic studies revealed that during myoblast fusion, the addition of GEP led to remarkable reductions in the expressions of muscle-specific transcription factors, including MyoD. In addition, the regulation of myotube formation by GEP is mediated by the anti-myogenic factor JunB, which is upregulated following GEP stimulation. Thus, GEP growth factor, JunB, and MyoD transcription factor form a regulatory loop and act in concert in the course of myogenesis.

Decreasing hydrophobicity or shielding hydrophobic areas of CH2 attenuates low pH-induced IgG4 aggregation.

Protein aggregation is a major challenge in the development of therapeutic monoclonal antibodies (mAbs). Several stressors can cause protein aggregation, including temperature shifts, mechanical forces, freezing-thawing cycles, oxidants, reductants, and extreme pH. When antibodies are exposed to low pH conditions, aggregation increases dramatically. However, low pH treatment is widely used in protein A affinity chromatography and low pH viral inactivation procedures. In the development of an IgG4 subclass antibody, mAb1-IgG4 showed a strong tendency to aggregate when temporarily exposed to low pH conditions. Our findings showed that the aggregation of mAb1-IgG4 under low pH conditions is determined by the stability of the Fc. The CH2 domain is the least stable domain in mAb1-IgG4. The L309E, Q311D, and Q311E mutations in the CH2 domain significantly reduced the aggregation propensity, which could be attributed to a reduction in the hydrophobicity of the CH2 domain. Protein stabilizers, such as sucrose and mannose, could also attenuate low pH-induced mAb1-IgG4 aggregation by shielding hydrophobic areas and increasing protein stability. Our findings provide valuable strategies for managing the aggregation of protein therapeutics with a human IgG4 backbone.

A VOSviewer-Based Bibliometric Analysis of Prescription Refills.

Purpose: Prescription refills are long-term prescriptions for chronic patients in stable status, which varies from country to country. A well-established prescription refill system is beneficial for chronic patients' medication management and facilitates the efficacy of clinical care. Therefore, we carried out a bibliometric analysis to examine the development of this field. Summary: Publications on prescription refills from 1970 to 2021 were collected in the Web of Science Core Collection (WoSCC). Search strategy TS = "prescri* refill*" OR "medi* refill*" OR "repeat prescri*" OR "repeat dispens*" OR TI = refill* was used for search. VOSviewer was applied to visualize the bibliometric analysis. A total of 319 publications were found in WoSCC. Study attention on prescription refills has shown a steady rise but is still low in recent years. The United States was the most productive country, which had the highest total citations, average citations per publication, and the highest H-index, and participated in international collaboration most frequently. The University of California system was the most productive institution. The U.S. Department of Veterans Affairs was the institution with the most citations, most average citation, and highest H-index. Sundell was the most productive author, and Steiner J. F. was the most influential author. "Adherence," "medication," and "therapy" were the most prominent keywords. Conclusion: Publications on prescription refills have increased rapidly and continue to grow. The United States had the leading position in the area. It is recommended to pay closer attention to the latest hotspots, such as "Opioids," "Surgery," "Differentiated care," and "HIV."

Effects of an mHealth Intervention for Pulmonary Tuberculosis Self-management Based on the Integrated Theory of Health Behavior Change: Randomized Controlled Trial.

BACKGROUND: Improving the health self-management level of patients with tuberculosis (TB) is significant for reducing drug resistance, improving the cure rate, and controlling the prevalence of TB. Mobile health (mHealth) interventions based on behavioral science theories may be promising to achieve this goal. OBJECTIVE: This study aims to explore and conduct an mHealth intervention based on the Integrated Theory of Health Behavior Change (ITHBC) in patients with pulmonary TB to increase their ability of self-care management. METHODS: A prospective randomized controlled study was conducted from May to November 2020. A total of 114 patients who were admitted consecutively to the TB clinic of Harbin Chest Hospital, China from May 2020 to August 2020 were recruited by convenience sampling. Patients were divided into the control group and intervention group, and all received a 3-month intervention. Patients in the intervention group and the control group received routine medical and nursing care in the TB clinic, including the supervision of their medications. In addition, pharmacist-assisted mHealth (WeChat) intervention based on the ITHBC theory about TB management was provided to the intervention group. The primary outcome was self-management behavior, while the secondary outcomes were TB awareness, self-efficacy, social support, and degree of satisfaction with health education. The outcomes were measured using web-based self-designed and standard questionnaires administered at baseline and at the end point of the study. Intergroup data were assessed using the Mann-Whitney U test, whereas intragroup data were assessed with the Wilcoxon test (for paired samples). RESULTS: A total of 112 patients (59 in intervention group and 53 in control group) completed the study. After the intervention, a statistically significant increase was noted in the scores of each item of self-care management behaviors compared with the scores at the baseline (P<.001) in the intervention group. The scores of all self-care management behaviors of the control group were lower than those of all self-care management behaviors in the intervention group (all P<.05), except for the item "cover your mouth and nose when coughing or sneezing" (P=.23) and item "wash hands properly" (P=.60), which had no statistically significant difference from those in the intervention group. Compared with those at baseline, TB knowledge awareness, self-efficacy, social support, and degree of satisfaction with health education in the intervention group increased significantly (P<.001), and the intervention group had significantly higher scores than the control group (P<.001). CONCLUSIONS: mHealth intervention for TB self-management based on ITHBC could deepen the understanding of patients with TB about their disease and improve their objective initiative and self-care management behaviors, which were beneficial for promoting compliance behavior and quality of prevention and control for pulmonary TB. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200055557; https://tinyurl.com/4ray3xnw.

The Influence of Parents on Medication Adherence of Their Children in China: A Cross-Sectional Online Investigation Based on Health Belief Model.

Objective: To explore the influence of parents on the medication adherence of their children. Study Design: A cross-sectional online investigation. Methods: A questionnaire with 41 questions was designed based on the health belief model (HBM) distributed and collected online in 28 cities around China through multi-stage stratified sampling. The reliability of the questionnaire was assessed with Cronbach's α coefficient and split-half reliability, and its validity was evaluated with exploratory factor analysis and content validity index. The structural equation model (SEM) was constructed to explore the relationship between the parents' health beliefs and their children's medication adherence. Subgroup analysis was conducted to study the differences between parents with different demographic characteristics (male and female, rural and urban). Results: 573 questionnaires were included for analysis, with an effective rate of 62.97%. The Cronbach'α coefficient of the questionnaire was 0.821 > 0.6, the split-half reliability was 0.651 > 0.6, the I-CVI of each dimension were >0.78, and the S-CVI/AVE (I-CVI average) was 0.95 > 0.9. The result of the questionnaire exploratory factor analysis met the standard. According to the SEM, self-efficacy (λ = 0.177), perceived susceptibility (λ = -0.244), and perceived severity (λ = 0.243) were direct influencing factors of children's medication adherence. In the subgroup analysis, the model established by each subgroup was consistent with the model established by the overall sample. The absolute values of females' perceived susceptibility, severity, and self-efficacy for their children's medication adherence path coefficients were higher than males'. Conclusion: Parents' perceived severity and self-efficacy may positively impact on their children's medication adherence, while parents' susceptibility to children's medication non-adherence may negatively impact on children's medication adherence. Objective constraints, perceived barriers, and benefits may in directly impact on children's medication adherence. Women's health beliefs appear to have a more significant impact on their children's medication adherence than men's. It may be an effective strategy to increase their children's medication adherence by improving parents' health beliefs. Medical staff should explain medication adherence knowledge to the parents of children, and inform the children of the possible consequences of non-adherence with medication, to improve the subjective perception of parents on the severity of children's non-adherence with medication, and improve parents' self-efficacy in rational medication for children. In addition, attention should be paid to the mental health of the parents, and more social and psychological support.

Granulin-epithelin precursor binds directly to ADAMTS-7 and ADAMTS-12 and inhibits their degradation of cartilage oligomeric matrix protein.

OBJECTIVE: To determine 1) whether a protein interaction network exists between granulin-epithelin precursor (GEP), ADAMTS-7/ADAMTS-12, and cartilage oligomeric matrix protein (COMP); 2) whether GEP interferes with the interactions between ADAMTS-7/ADAMTS-12 metalloproteinases and COMP substrate, including the cleavage of COMP; 3) whether GEP affects tumor necrosis factor alpha (TNFalpha)-mediated induction of ADAMTS-7/ADAMTS-12 expression and COMP degradation; and 4) whether GEP levels are altered during the progression of arthritis. METHODS: Yeast two-hybrid, in vitro glutathione S-transferase pull-down, and coimmunoprecipitation assays were used to 1) examine the interactions between GEP, ADAMTS-7/ADAMTS-12, and COMP, and 2) map the binding sites required for the interactions between GEP and ADAMTS-7/ADAMTS-12. Immunofluorescence cell staining was performed to visualize the subcellular localization of GEP and ADAMTS-7/ADAMTS-12. An in vitro digestion assay was employed to determine whether GEP inhibits ADAMTS-7/ADAMTS-12-mediated digestion of COMP. The role of GEP in inhibiting TNFalpha-induced ADAMTS-7/ADAMTS-12 expression and COMP degradation in cartilage explants was also analyzed. RESULTS: GEP bound directly to ADAMTS-7 and ADAMTS-12 in vitro and in chondrocytes, and the 4 C-terminal thrombospondin motifs of ADAMTS-7/ADAMTS-12 and each granulin unit of GEP mediated their interactions. Additionally, GEP colocalized with ADAMTS-7 and ADAMTS-12 on the cell surface of chondrocytes. More importantly, GEP inhibited COMP degradation by ADAMTS-7/ADAMTS-12 in a dose-dependent manner through 1) competitive inhibition through direct protein-protein interactions with ADAMTS-7/ADAMTS-12 and COMP, and 2) inhibition of TNFalpha-induced ADAMTS-7/ADAMTS-12 expression. Furthermore, GEP levels were significantly elevated in patients with either osteoarthritis or rheumatoid arthritis. CONCLUSION: Our observations demonstrate a novel protein-protein interaction network between GEP, ADAMTS-7/ADAMTS-12, and COMP. Furthermore, GEP is a novel specific inhibitor of ADAMTS-7/ADAMTS-12-mediated COMP degradation and may play a significant role in preventing the destruction of joint cartilage in arthritis.

Knowledge, attitude and practices regarding health self-management among patients with osteogenesis imperfecta in China: an online cross-sectional survey.

OBJECTIVES: Assessing the knowledge, attitude and practices (KAP) regarding health self-management among patients with osteogenesis imperfecta (OI) in China. DESIGN: An online cross-sectional survey. SETTING: A structured questionnaire was distributed online through China-Dolls Center for Rare Disorders (CCRD), a non-governmental charity in China. PARTICIPANTS: Participants were all patients with OI from CCRD. After stratified sampling according to the economic level of residential city, 901 patients were proportionally selected and 869 patients completed the survey (response rate: 96.4%). MAIN OUTCOME MEASURES: Demographic characteristics and KAP information were gathered using a 5-point Likert scale. The score of each dimension of KAP was the sum of the scores of all included items. Χ2 test or Fisher's exact test was used to compare scores of different items. Ordinal regression was employed to determine the significant factors influencing KAP. RESULTS: A total of 802 questionnaires were included for analysis. Male respondents accounted for 57.1%, and 29.1% of respondents were of 26~30 years. More than half (50~60%) of patients knew the main symptoms of OI and the treatment of OI-related complications. Almost 80% of patients showed positive attitude. Nearly 60~70% of the patients were relatively able to take appropriate practice regarding OI management. There was a significant correlation between scores of knowledge and attitude, attitude and practice, as well as knowledge and practice. Patients aged 26~30 years, from urban areas and big cities, had higher KAP scores. Male patients showed better performance in knowledge, and highly educated patients perform better in practice. CONCLUSIONS: Patients with OI did not have sufficient knowledge on disease care and up-to-date caring guidelines, and their practice regarding health self-management also needs to be improved. Gender, age, educational level and economic level of residence can affect the level of KAP for patients, thus developing targeted and tailored programmes for patients with OI is highly recommended.

Delta/Notch-Like EGF-Related Receptor (DNER) Is Not a Notch Ligand.

Delta/Notch-like EGF-related receptor (DNER) has been reported to act as a Notch ligand, despite lacking a Delta/Serrate/Lag (DSL) binding domain common to all other known ligands. The established Notch ligand Delta-like 1 (DLL1), but not DNER, activated Notch1 in a luciferase assay, prevented the differentiation of myoblasts through Notch signaling, and bound Notch-fc in a cell-based assay. DNER is not a Notch ligand and its true function remains unknown.

Caspr2 autoantibodies target multiple epitopes.

OBJECTIVE: To better understand the mechanisms of autoantibodies to the axonal protein contactin-associated protein-like 2 (Caspr2) by studying their target epitopes. METHODS: A plasmid for expressing Caspr2 was modified so that the various extracellular subdomains were deleted individually and in groups. Cultured cells were transfected to express these constructs and assayed by immunofluorescence staining with a commercial Caspr2 antibody and a panel of patient sera known to react with Caspr2. Western blotting was also performed. The role of glycosylation in immunogenicity was tested with tunicamycin and PNGase F treatment. RESULTS: Patient antibodies bound to the extracellular domain of Caspr2. Neither native protein structure nor glycosylation was required for immunoreactivity. Caspr2 constructs with single or multidomain deletions were expressed on the plasma membrane. All deletion constructs were recognized by patients' sera, although reactivity was significantly reduced with deletion of the discoidin-like subdomain and strongly reduced or abolished with larger deletions of multiple N-terminal subdomains. Caspr2 with all subdomains deleted except the discoidin-like domain was still recognized by the antibodies. CONCLUSION: Caspr2 autoantibodies recognize multiple target epitopes in the extracellular domain of Caspr2, including one in the discoidin-like domain. Reactivity for some epitopes is not dependent on glycosylation or native protein structure.

Antibodies to Delta/notch-like epidermal growth factor-related receptor in patients with anti-Tr, paraneoplastic cerebellar degeneration, and Hodgkin lymphoma.

IMPORTANCE: The anti-Tr immune response is associated with paraneoplastic cerebellar degeneration and Hodgkin lymphoma (HL). One case series has reported that the Delta/notch-like epidermal growth factor-related receptor (DNER) is the actual target for anti-Tr antibodies, but this result has not been replicated. OBJECTIVE: To describe a patient with anti-Tr and confirm that DNER is the autoantigen for a series of patients with anti-Tr. DESIGN, SETTING, AND PARTICIPANTS: Observational study and analysis of biological samples for antibodies to DNER at the hospital of the University of Pennsylvania. We examined a cerebrospinal fluid sample from 1 patient with anti-Tr and serum and/or cerebrospinal fluid samples from 5 other patients with anti-Tr. EXPOSURE: Transfection of HEK293T and Hela cells to express DNER coupled to an enhanced green fluorescent protein tag using a plasmid previously used to detect human DNER antibodies. RESULTS: A man in his 30s with paraneoplastic cerebellar degeneration and anti-Tr underwent treatment with corticosteroids and intravenous immunoglobulin, resulting in clinical improvement before chemotherapy. Despite close oncologic follow-up, a biopsy, positron emission tomography, and computed tomography, he was not diagnosed as having HL until 6 months after symptom onset. The cerebrospinal fluid sample from this patient reacted with cells transfected to express DNER, as did cerebrospinal fluid and/or serum samples from 5 other patients with paraneoplastic cerebellar degeneration, HL, and anti-Tr. Only 4 of the 5 serum samples reacted to permeabilized cells enough to be distinguished from background, but all 5 serum samples convincingly labeled live cells, which had considerably less background. All 6 control serum samples and 1 serum sample from a patient previously diagnosed as having anti-Tr (but without HL or cerebellitis) did not recognize DNER. CONCLUSIONS AND RELEVANCE: This case demonstrates the importance of testing for the anti-Tr immune response in patients with cerebellar degeneration. The strong association of anti-Tr with HL requires careful surveillance for this tumor. We also confirm that DNER is the target antigen of the anti-Tr immune response. Screening for DNER antibodies against living transfected cells may offer an improved signal-to-noise characteristic compared with immunostaining of fixed, permeabilized cells.

The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice.

The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFα-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFα signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis.