Search

Background In the long-term use of multiple medications for elderly patients diagnosed with chronic diseases, medication problems are prominent, which seriously reduces their quality of life. The burden of medications of patients critically affects their medication beliefs, behaviors and disease outcomes. It may be a solution to stress the burden of medications of patients. Its medication issues develops a novel perspective. The present study aimed to exploit the Chinese version of Living with Medicines Questionnaire-3(C-LMQ-3) to quantify the medicines burden of elderly patients diagnosed with chronic diseases in China, and evaluate the relevant demographic characteristics of sub-populations with high medicines burden. Methods The survey was distributed to elderly patients aged ≥ 60 years with chronic disease by using ≥ 5 medicines, C-LMQ-3 scores and domain scores were compared by the characteristics of elderly patients by employing descriptive statistics and performing statistical tests. Results On the whole, 430 responses were analyzed, and the participants were aged between 60 and 91 years, with the average age of 73.57 years (SD: 7.87). Most of the responses were female (61.7 %) with middle school education (38.5 %). Moreover, 54.1 % of the participants lived with spouse only, 16.2 % had both spouse and children, and 10.0 % lived alone. As indicated from regression analysis, higher C-LMQ-3 scores were associated with those who were with low education level, 60–69 years-old, using ≥ 11 medicines, using medicines ≥ 3 times a day, income per month (RMB) ≤ 3000, and who having higher monthly self-paid medication (RMB) ≥ 300 (p Conclusions This study presents the preliminary evidence to elderly patients diagnosed with chronic diseases in mainland China that pay attention to multiple medications burden may help reduce the Drug Related Problems, whereas some elderly patients have a higher burden of medication. Chinese health care providers are required to primarily evaluate and highlight such patients, and formulate relevant intervention strategies to ensure medication adherence and daily medication management of elderly patients with polypharmacy.

Carcinoma cuniculatum (CC) is a rare and well-differentiated clinicopathological variant of squamous cell carcinoma (SCC) that is not common in head and neck. It is defined histologically by the infiltrative pattern of a deep, broad, and complex proliferation of stratified squamous epithelium with keratin cores and keratin-filled crypts. It has a propensity for local invasion and rare metastasis. This case report describes a 39-year-old man who was referred to our hospital with painful swelling in the right maxillary gingiva for 1 month and restriction of mouth opening for 1 week. Two biopsy examinations were negative for the diagnosis of malignancy, and the patient was misdiagnosed with verruciform xanthoma before an accurate diagnosis of CC. The biopsy reports were not in line with the imaging findings and clinical manifestations. Finally, he was diagnosed based on the combination of clinical manifestations and the pathological findings. Our case report provided a thorough clinical and histopathologic case of CC in maxillary gingiva, together with a brief review of the literature. In addition, we highlighted the difficulties in arriving at this uncommon diagnosis, and discussed the diagnosis of CC based on the combination of clinical manifestations and the pathological findings. To our knowledge, this is a very rare case of CC of the gingiva mimicking verruciform xanthoma.

Background Adenoid cystic carcinoma (ACC) is a rare cancer with an aggressive phenotype and the high incidence of recurrence and distant metastasis severely affects the overall survival of ACC patients. Understanding the molecular mechanisms that drives ACC could improve the treatment and outcomes of patients with this disease. Methods Actionable genetic alterations in 52 surgically resected ACC tissue samples were identified using targeted next generation sequencing (NGS). Expression of c-KIT/PDGFRα/VEGFR2 was assessed by immunohistochemistry (IHC). Sunitinib, a multi-targeted small molecule inhibitor of receptor tyrosine kinases (RTKs), was used off-label in one ACC patient harboring the KIT/PDGFRA/KDR amplification. Results Potentially actionable genetic alterations were detected in 61.5% (32/52) of patients. In addition to the common actionable targets identified in NOTCH signaling and FGF/PI3K pathway, multiple novel gene fusions were detected in 7.7% (4/52) of ACC patients. Specifically, the KIT/PDGFRA/KDR amplification was identified in 2 of 52 (3.8%) cases and triple positive c-KIT/PDGFRα/VEGFR2 by IHC was associated with a significantly higher likelihood of distant metastasis. Furthermore, an advanced ACC patient with the KIT/PDGFRA/KDR amplification and who was positive for three encoded proteins showed a partial response to sunitinib. Conclusions A total of 61.5% of ACC patients were found to harbor at least one actionable genetic alteration via a targeted NGS in this study. The KIT/PDGFRA/KDR amplification as well as triple positive c-KIT/PDGFRα/VEGFR2 defined a distinctive molecular phenotype that was characterized by distant metastasis. Clinical trials investigating the application of RTKs in ACC patients with the KIT/PDGFRA/KDR amplification or triple positive c-KIT/PDGFRα/VEGFR2 are warranted.

Background: Progressive retinal neuroaxonal damage after acute optic neuritis may occur in neuromyelitis optica spectrum disorder (NMOSD). However, it is unclear if treatments used to prevent attacks influence neurodegeneration.Objectives: We aimed to investigate retinal damage in patients treated with disease-modifying drugs in a longitudinal study.Methods: We retrospectively included 50 patients with aquaporin 4-antibody-seropositive NMOSD. Peripapillary retinal nerve fiber layer (pRNFL) thickness, macular ganglion cell complex (mGCC) thickness, total macular volume (TMV), and optic disc measures were acquired by spectral domain optical coherence tomography in patients treated with tocilizumab, rituximab, and azathioprine.Results: Longitudinally, in eyes with a history of ON (NMOSDON+), we observed annual thinning of mGCC [tocilizumab: −1.77 (−3.44, −0.09) μm, p = 0.041; rituximab: −2.03 (−3.58, −0.48) μm, p = 0.017; azathioprine: −1.79 (−2.22, −1.37) μm, p < 0.001], and pRNFL [tocilizumab: −2.07 (−0.75, −3.39) μm, p = 0.005; rituximab: −2.18 (−0.36, −4.00) μm, p = 0.023; azathioprine: −2.37 (−0.98, −3.75) μm, p = 0.003], reduced TMV [tocilizumab: −0.12 (−0.22, −0.01) mm3, p = 0.028; rituximab: −0.15 (−0.21, −0.08) mm3, p = 0.001; azathioprine: −0.12 (−0.20, −0.04) mm3, p = 0.006], and increased cup area [tocilizumab: 0.08 (−0.01, 0.16) mm2, p = 0.010; rituximab: 0.07 (0.01, 0.12) mm2, p = 0.019; azathioprine: 0.14 (0.02, 0.26) mm2, p = 0.023]. However, we detected no significant differences in annual changes in mGCC, pRNFL, TMV, and cup area between patients with tocilizumab, rituximab, and azathioprine in NMOSDON+ eyes. NMOSDON− eyes did not display mGCC or pRNFL thinning in patients treated with tocilizumab and rituximab. Intriguingly, we observed significant thinning of mGCC in patients treated with azathioprine compared with tocilizumab [−0.84 (−1.50, −0.18) μm vs. −0.19 (−0.87, 0.48) μm, p = 0.012] and rituximab [−0.84 (−1.50, −0.18) μm vs. −0.07 (−1.25, −2.51) μm, p = 0.015] in NMOSDON− eyes.Conclusions: This study demonstrated that retinal ganglion cell loss is independent of ON attacks in NMOSD. Tocilizumab and rituximab may delay mGCC thinning in NMOSDON− eyes compared with azathioprine.

Tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, showed its therapeutic efficacy on neuromyelitis optica spectrum disorder (NMOSD). To assess the immunological effects of this drug on B cells, follicular T helper (Tfh) cells, and peripheral T helper (Tph) cells in patients with NMOSD, peripheral B cell and Tfh cell phenotypes were evaluated in 26 patients with NMOSD before and after tocilizumab treatment by nine-color flow cytometry, as well as the expression of costimulatory and co-inhibitory molecules on B cells. Results showed that the frequency of CD27+IgD− switched memory B cells, CD27-IgD- double-negative B cells, and CD27highCD38high antibody-secreting cells was increased in patients with NMOSD. Tocilizumab treatment led to a significant shift of B cells to naïve B cells from memory B cells after 3 months. Three markers on B cells associated with T-cell activation (i.e., CD86 CD69, and HLA-DR) were downregulated after tocilizumab treatment. The frequencies of total Tfh and Tph cells were decreased, whereas that of follicular regulatory T cells tended to increase. Intrinsic increased PD-L1 and PD-L2 expression was characteristic of B cells in patients with NMOSD. Tocilizumab selectively restored PD-L1 on B-cell subsets. These results provided evidence that tocilizumab enhanced B- and T-cell homoeostasis by regulating B-cell differentiation and inhibiting lymphocyte activation in patients with NMOSD.

Background and ObjectivesTo assess the molecular landscape of B-cell subpopulations across different compartments in patients with neuromyelitis optica spectrum disorder (NMOSD).MethodsWe performed B-cell transcriptomic profiles via single-cell RNA sequencing across CSF, blood, and bone marrow in patients with NMOSD.ResultsAcross the tissue types tested, 4 major subpopulations of B cells with distinct signatures were identified: naive B cells, memory B cells, age-associated B cells, and antibody-secreting cells (ASCs). NMOSD B cells show proinflammatory activity and increased expression of chemokine receptor genes (CXCR3 and CXCR4). Circulating B cells display an increase of antigen presentation markers (CD40 and CD83), as well as activation signatures (FOS, CD69, and JUN). In contrast, the bone marrow B-cell population contains a large ASC fraction with increased oxidative and metabolic activity reflected by COX genes and ATP synthase genes. Typically, NMOSD B cells become hyperresponsive to type I interferon, which facilitates B-cell maturation and anti–aquaporin-4 autoantibody production. The pool of ASCs in blood and CSF were significantly elevated in NMOSD. Both CD19− and CD19+ ASCs could be ablated by tocilizumab, but not rituximab treatment in NMOSD.DiscussionB cells are compartmentally fine tuned toward autoreactivity in NMOSD and become hyperreactive to type I interferon. Inhibition of type I interferon pathway may provide a new therapeutic avenue for NMOSD.

Background: Recent studies report that hospital staff at the forefront of caring for COVID-19 patients experience increased psychological distress. To effectively manage the outbreak of COVID-19, China established COVID-19 designated and non-designated hospitals. To date, few studies have examined the impacts of COVID-19 on psychological health of staff working at non-designated hospitals. This study is to explore factors affecting psychological health of non-designated hospital staff in China during the COVID-19 pandemic.Methods: Data were collected through an online questionnaire between February and March 2020. The questionnaire consists of General Health Questionnaire (GHQ-20), Social Support Rating Scale (SSRS), Simplified Coping Style Questionnaire (SCSQ), sociodemographic characteristics, employment history, health status, and contact history of COVID-19. The questionnaire was distributed through hospital WeChat groups and work colleague referrals. A total of 470 non-designated hospital staff members completed the questionnaire. Multiple Linear Regression analysis was used to interpret the associations among social support, coping styles, sociodemographic factors, job roles, and psychological status. Data were analyzed using SPSS version 21.0.Results: The non-designated hospital staff differed significantly in anxiety and depression subscores of the GHQ-20 by their job roles, levels of social support, and history of mental disorders. Staff with medical job roles, good self-reported health status, no previous mental disorders, adequate social support, and positive coping styles scored lower in GHQ-20 total score, which indicated healthier psychological status.Conclusions: The results indicate that history of mental health disorders, non-medical job roles, and inadequate social support are associated with greater psychological distress. Personalized support should be provided to those who are vulnerable and in need of social and psychological support.

BackgroundInterleukin-6 receptor blockade is effective in reducing the risk of relapses in neuromyelitis optica spectrum disorder (NMOSD). However, its efficacy during acute attacks of NMOSD remains elusive.ObjectiveWe investigated the effects of tocilizumab on disability during acute attacks, as well as its maintenance, in patients with moderate-to-severe myelitis.MethodsNineteen patients with NMOSD received tocilizumab treatment as add-on to high-dose methylprednisolone (HDMP) in acute myelitis and twenty-two patients who only received HDMP were compared. Disease disability was assessed using a multi-level scaling system that included the expanded disability status scale (EDSS), Hauser ambulation index (HAI), modified Rankin scale (mRS), pain numerical rating scale (NRS), functional assessment of chronic illness therapy-fatigue scale (FACIT-F), activity of daily living (ADL), EuroQol five-dimensions-three-level questionnaire (EQ-5D-3L), and sensory function score and bowel and bladder function score in Kurtzke functional systems scores (FSS).ResultsImproved EDSS, HAI, and mRS, as well as increased ADL and EQ-5D-3L were significant in patients on tocilizumab compared with those on steroids as monotherapy at 3 months (p < 0.05). Both groups of patients showed improved pain, fatigue, sensory function, and autonomic function at follow-ups, compared with baseline respectively. The changes in NRS, FACIT-F, and sensory and autonomic FSS showed no significant differences between the two groups. Tocilizumab significantly lowered the risk of relapses (HR = 0.21, 95% CI 0.06–0.76, p = 0.017) and reduced the annualized relapse rate compared with those by steroids (0.1 ± 0.2 vs 0.5 ± 0.6, p = 0.013).ConclusionEarly initiation of tocilizumab provided a safe and effective add-on alternative during attacks, and its maintenance contributed to a significant reduction of relapse rate in NMOSD.

To formulate a xanthan gum–containing linezolid ophthalmic solution (LZD-XG) as a new antibiotic treatment against ocular bacterial infection. LZD-XG was prepared and evaluated for its in vitro/in vivo ocular tolerance, in vitro/in vivo antibacterial activity, and in vivo ocular penetration. The optimized LZD-XG exhibited good in vitro/in vivo eye tolerance. A prolonged ocular surface residence time of LZD-XG was observed after topical instillation, and the ocular permeation was significantly better for LZD-XG than fora linezolid (LZD) ophthalmic solution. The in vitro antimicrobial activity was significantly better with LZD-XG than with LZD. In vivo evaluation also confirmed a strong therapeutic treatment effect of LZD-XG, as it significantly improved the clinical symptoms, ameliorated the damage of Staphylococcus aureus to ocular tissues, lowered the colony forming unit counts in the cornea, and decreased the myeloperoxidase activity in the cornea. LZD-XG was deemed a viable ophthalmic solution against ocular bacterial infection due to its excellent in vitro and in vivo characterizations.

The aim of this retrospective case series study was to evaluate the response and durability of rituximab in patients with new-onset acetylcholine receptor positive (AChR +) generalized myasthenia gravis (MG). Patients were initiated with low-dose rituximab treatment within 3.5 months of onset without concomitant oral immunosuppressants. Seventeen patients (89%) remained relapse-free with a mean follow-up of 51.3 months. Clinical improvement was observed in parallel with the maintenance of low-dose corticosteroids or the complete discontinuation of corticosteroids. Long-term depletion of B cells with low-dose rituximab treatment has shown favorable efficacy and tolerance in reducing disease activity for AChR+ generalized MG.

Objectives: A frequent emergence of drug resistance has been observed and posed great threat to global public health recently. This work aimed to investigate the potential synergistic effect and the underlying mechanisms of AgNPs-fluconazole combination more extensively through 2 clinically isolated fluconazole-resistant Candida albicans (C. albicans) strains.Methods: Antifungal properties of AgNPs and fluconazole alone or together against planktonic cells and biofilms were tested. Cellular and molecular targets associated with fluconazole resistance were monitored after AgNPs treatment. Antifungal potential of AgNPs-fluconazole combination was also explored in vivo using a mouse model of disseminated candidiasis. Tissue burden and survival rate were analyzed. Results: The results indicated that AgNPs worked synergistically with fluconazole against both planktonic cells of fluconazole-resistant C. albicans and biofilms formed < 12 hours. AgNPs treatment down-regulated ERG1, ERG11, ERG25, and CDR2, decreased membrane ergosterol levels and membrane fluidity, reduced membrane content of Cdr1p, Cdr2p, and thus efflux bump activity. The elevated ROS production was also a likely cause of the synergistic effect. In vivo, AgNPs and fluconazole combination significantly decreased the fungal burden and improved the survival rate of infected mice. Conclusion: In conclusion, these results further confirm that AgNPs-fluconazole combination is a hopeful strategy for the treatment of fluconazole-resistant fungal infections.

Azathioprine is used as a first-line treatment to prevent relapses of neuromyelitis optica spectrum disorder (NMOSD). Tocilizumab has been reported to reduce NMOSD disease activity in retrospective case reports. We aimed to compare the safety and efficacy of tocilizumab and azathioprine in patients with highly relapsing NMOSD.We did an open-label, multicentre, randomised, phase 2 trial at six hospitals in China. We recruited adult patients (aged ≥18 years) with highly relapsing NMOSD diagnosed according to 2015 International Panel for Neuromyelitis Optica Diagnosis criteria, who had an Expanded Disability Status Scale (EDSS) score of 7·5 or lower, and had a history of at least two clinical relapses during the previous 12 months or three relapses during the previous 24 months with at least one relapse within the previous 12 months. Patients were randomly assigned (1:1) to intravenous tocilizumab (8 mg/kg every 4 weeks) or oral azathioprine (2-3 mg/kg per day) by an independent statistician using computer-generated randomisation software with permuted blocks of four. The central review committee, EDSS raters, laboratory personnel, and radiologists were masked to the treatment assignment, but investigators and patients were aware of treatment allocation. The minimum planned duration of treatment was 60 weeks following randomisation. The primary outcome was time to first relapse in the full analysis set, which included all randomly assigned patients who received at least one dose of study drug, and the per-protocol population, which included all patients who used azathioprine or tocilizumab as monotherapy. For the analyses of the primary outcome, the patients were prespecified into two subgroups according to concomitant autoimmune disease status. Safety was assessed in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03350633.Between Nov 1, 2017, and Aug 3, 2018, we enrolled 118 patients, of whom 59 were randomly assigned to tocilizumab and 59 were randomly assigned to azathioprine. All 118 patients received one dose of study drug and were included in the full analysis set. 108 participants were included in the per-protocol analysis (56 in the tocilizumab group and 52 in the azathioprine group). In the full analysis set, median time to the first relapse was longer in the tocilizumab group than the azathioprine group (78·9 weeks [IQR 58·3-90·6] vs 56·7 [32·9-81·7] weeks; p=0·0026). Eight (14%) of 59 patients in the tocilizumab group and 28 (47%) of 59 patients in the azathioprine group had a relapse at the end of the study (hazard ratio [HR] 0·236 [95% CI 0·107-0·518]; p0·0001). In the per-protocol analysis, 50 (89%) of 56 patients in the tocilizumab group were relapse-free compared with 29 (56%) of 52 patients in the azathioprine group at the end of the study (HR 0·188 [95% CI 0·076-0·463]; p0·0001); the median time to first relapse was also longer in the tocilizumab group than the azathioprine group (67·2 weeks [IQR 47·9-77·9] vs 38·0 [23·6-64·9]; p0·0001). In the prespecified subgroup analysis of the full analysis set stratified by concomitant autoimmune diseases, among patients without concomitant autoimmune diseases, three (9%) of 34 patients in the tocilizumab group and 13 (35%) of 37 patients in the azathioprine group had relapsed by the end of the study. Among patients with concomitant autoimmune diseases, a lower proportion of patients in the tocilizumab group had a relapse than in the azathioprine group (five [20%] of 25 patients vs 15 [68%] of 22 patients; HR 0·192 [95% CI 0·070-0·531]; p=0·0004). 57 (97%) of 59 patients in the tocilizumab group and 56 (95%) of 59 patients in the azathioprine group had adverse events. Treatment-associated adverse events occurred in 36 (61%) of 59 tocilizumab-treated patients and 49 (83%) of 59 azathioprine-treated patients. One death (2%) occurred in the tocilizumab group and one (2%) in the azathioprine group, but neither of the deaths were treatment-related.Tocilizumab significantly reduced the risk of a subsequent NMOSD relapse compared with azathioprine. Tocilizumab might therefore be another safe and effective treatment to prevent relapses in patients with NMOSD.Tianjin Medical University, Advanced Innovation Center for Human Brain Protection, National Key Research and Development Program of China, National Science Foundation of China.

Background Evidence suggests that brain infiltration of lymphocytes contributes to acute neural injury after cerebral ischemia. However, the spatio-temporal dynamics of brain-infiltrating lymphocytes during the late stage after cerebral ischemia remains unclear. Methods C57BL/6 (B6) mice were subjected to sham, photothrombosis, or 60-min transient middle cerebral artery occlusion (MCAO) procedures. Infarct volume, neurodeficits, production of reactive oxygen species (ROS) and inflammatory factors, brain-infiltrating lymphocytes, and their activation as well as pro-inflammatory cytokine IFN-γ production were assessed. Brain-infiltrating lymphocytes were also measured in tissue sections from post-mortem patients after ischemic stroke by immunostaining. Results In mice subjected to transient MCAO or photothrombotic stroke, we found that lymphocyte infiltration persists in the ischemic brain until at least day 14 after surgery, during which brain infarct volume significantly diminished. These brain-infiltrating lymphocytes express activation marker CD69 and produce proinflammatory cytokines such as IFN-γ, accompanied with a sustained increase of reactive oxygen species (ROS) and inflammatory cytokines release in the brain. In addition, brain-infiltrating lymphocytes were observed in post-mortem brain sections from patients during the late stage of ischemic stroke. Conclusion Our results demonstrate that brain-infiltration of lymphocytes persists after the acute stage of cerebral ischemia, facilitating future advanced studies to reveal the precise role of lymphocytes during late stage of stroke. Electronic supplementary material The online version of this article (10.1186/s12974-017-1017-0) contains supplementary material, which is available to authorized users.

Myelin oligodendrocyte glycoprotein-immunoglobulin (MOG-IgG) associated disorder (MOGAD) has been recognized as a distinct disease entity with recurrent attacks. But the standard therapeutic approach to reduce relapses is unknown. Different doses of mycophenolate mofetil (MMF) are frequently used in MOGAD. We aimed to investigate the response to stratified doses of MMF in adult patients with MOGAD.We determined the frequency of relapses in patients receiving various doses of MMF treatment for MOGAD. Patients were reviewed for relapses before and during long-term treatment. Cox proportional hazards models were used to analyze the correlation between the MMF dosage and the annualized relapse rate (ARR) as well as clinical features.22 patients receiving low-dose MMF (1000 mg/day), 19 patients receiving moderate-dose MMF (1000 mg/day ≤ MMF dose2000 mg/day) and 21 patients receiving high-dose MMF (≥ 2000 mg/day) were collected in our cohort. Cox regression analysis showed that high-dose MMF treatment significantly reduced the risk of relapses (HR 0.501 [95% CI 0.268-0.934], p = 0.030) compared with low-dose and moderate-dose of MMF treatment, after adjusted by age, gender, disease duration and prednisone therapy. Patients (13/62) concomitant with autoimmune diseases, had a higher proportion of relapses (76.92%) compared with those without autoimmune diseases (18.37%) (HR = 5.96, 95% CI 1.73-20.48, p 0.001). The overall median ARR reduced from 1.13 to 0.32 under high-dose MMF treatment (p = 0.004). However, there was no significant reduction in ARR either in patients with low-dose or those with moderate-dose of MMF.This study suggests that high-dose of MMF treatment may reduce recurrent demyelinating attacks, with the lowest ARR. Randomized controlled studies are required to validate the effective therapeutic regimen.

Background Despite inclusion in neuromyelitis optica spectrum disorders (NMOSD), myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated diseases are increasingly recognized as an independent disease entity. In this study, we conducted a systematic review and meta-analysis to comprehensively update the rate of occurrence of MOG-Ab in Aquaporin4 (AQP4)-antibody seronegative NMOSD. Methods We searched PubMed, EMBASE, and Cochrane databases for studies reporting the rates of patients with MOG-Ab in NMOSD. Fixed or random-effects models were used to pool results across studies. Results Fourteen studies met the inclusion criteria. Overall, MOG-Abs positive patients comprised 9.3% of all NMO/NMOSD (95% confidence interval [CI] 7.9%–10.8%, I2 = 13.1%), 32.5% of all AQP4-Ab seronegative NMO/NMOSD (95% CI 25.7%–39.3%, I2 = 45.8%), and 41.6% of AQP4-Ab seronegative NMOSD cases diagnosed by IPND 2015 criteria (95% CI 35.1%–48.2%, I2 = 0.0%). The pooled prevalence of MOG-Ab was 31.0% among Asian AQP4-Ab seronegative NMO/NMOSD patients (95% CI 22.1%–39.9% I2=54.1%) and 34.3% in European seronegative NMO/NMOSD (95% CI 21.9%–46.7%, I2 = 51.9%). Conclusions This study shows that MOG-Abs represent a substantial proportion of AQP4-Ab seronegative NMOSD patients despite different underlying mechanisms, clinical manifestations, and treatment response, suggesting MOG-Ab screening in AQP4-Ab seronegative NMOSD patients can facilitate accurate diagnoses and treatments.

Aims Intracerebral hemorrhage (ICH) is a devastating type of stroke without specific treatment. Activator protein 1 (AP‐1), as a gene regulator, initiates cytokine expression in response to environmental stimuli. In this study, we investigated the relationship between AP‐1 and neuroinflammation‐associated brain injury triggered by ICH. Methods Intracerebral hemorrhage mice were developed by autologous blood or collagenase infusion. We measured the dynamics of AP‐1 in mouse brain tissues during neuroinflammation formation after ICH. The effects of the AP‐1 inhibitor SR11302 on brain injury and neuroinflammation as well as the underlying mechanisms were investigated in vivo and in vitro. Results AP‐1 was significantly upregulated in mouse brain tissue as early as 6 hours after ICH, accompanied by elevations in proinflammatory factors, including interleukin (IL)‐6, IL‐1β, and tumor necrosis factor (TNF)‐α. Inhibition of AP‐1 using SR11302 reduced neurodeficits and brain edema at day 3 after ICH. SR11302 ablated microglial IL‐6 and TNF‐α production and brain‐infiltrating leukocytes in ICH mice. In addition, SR11302 treatment diminished thrombin‐induced production of IL‐6 and TNF‐α in cultured microglia. Conclusions Inhibition of AP‐1 curbs neuroinflammation and reduces brain injury following ICH.

A series of magnetic activated carbon nanospheres (MACSs) were synthesized via a simple one-step hydrothermal and pyrolysis method. The characterization results confirm that the shell-core structured MACSs were formed because of Fe3O4 nanoparticles (Fe3O4NPs) mostly dispersed on the surface of activated carbon nanospheres. This structure can not only effectively prevent the agglomeration of activated carbon, but can provide a sufficient magnetism for recycle via the magnetic assisted separation technology. Batch tests for methylene blue (MB) removal show that an excellent adsorption capacity of 192.64 mg g−1 at 298 K can be obtained on MACS-700, which can be kept up to 156.4 mg g−1 even after five cycles. The adsorption isotherm and kinetics results show that the adsorption behavior can be well described by Langmuir isotherm model and the experimental data fit better for the pseudo-second-order kinetic model. It demonstrate that the adsorption rate of MB mainly controlled by chemical-adsorption, meanwhile, effects of external mass transfer and intra particle diffusion also can be found.

Background: Neurofilament light chain (NfL) and glial fibrilliary acidic protein (GFAP) have been suggested to be biomarkers of the pathophysiological process of neuromyelitis optica spectrum disorders (NMOSD), but the relationship between the plasma levels of these molecules with disease activity and treatment is incompletely understood. Objective: To investigate the treatment effects of disease-modifying drugs on plasma neurofilament light chain (pNfL) and plasma glial fibrillary acidic protein (pGFAP) and explore the predictive value of pNfL and pGFAP in the activity of NMOSD. Methods: pNfL and pGFAP levels were measured using single-molecule arrays in 72 patients with NMOSD and 38 healthy controls (HCs). Patients with NMOSD received tocilizumab ( n = 29), rituximab ( n = 23), oral prednisone ( n = 16), and oral azathioprine or mycophenolate mofetil ( n = 4). Results: NMOSD patients had significantly higher pNfL and pGFAP levels than HCs (pNfL, 18.3 (11.2–39.3) versus 11.5 (7.0–23.3) pg/mL; p = 0.001; pGFAP, 149.7 (88.6–406.5) versus 68.7 (59.4–80.8) pg/mL; p Conclusion: pNfL and pGFAP may serve as biomarkers for NMOSD disease activity and treatment effects.

Commercial grade weakly basic resin D301 was impregnated with iron through a simple method using ferric chloride. Experiments for single, bisolute and trinary competitive adsorption were carried out to investigate the adsorption behavior of 2-naphthalenesulfonic acid (NSA), sulfuric acid and sulfurous acid from their solution at 298K onto the novel hybrid iron impregnated D301(Fe-D301). Adsorption affinity of NSA on Fe-D301 was found to be much higher than that of sulfuric acid, while adsorption affinity of sulfuric acid was slightly higher than that of sulfurous acid. The data of single-solute adsorption were fitted to the Langmuir model and the Freundlich adsorption model. The non-ideal competitive adsorbed model coupled with the single-solute adsorption models were used to predict the bisolute and trinary-solute competitive adsorption equilibria. The NICM coupled with the Langmuir model yields the favorable representation of the bisolute and trinary-solute competitive adsorption behavior.

Background During acute attacks of neuromyelitis optica spectrum disorder (NMOSD), intravenous immunoglobulin (IVIG) maybe useful building on experience treating autoimmune disorders. Methods We conducted a retrospective study of several treatment modes for NMOSD attacks at Beijing Tiantan Hospital and Tianjin Medical University General Hospital. Clinical outcomes were defined as the short-term remission status. The good (GR), moderate (MR) or poor remission (PR) was respectively defined to triple-grade based on percentage change of initial and follow-up Expanded Disability Status Scale (EDSS) scores. Results A total of 243 attacks was analyzed in 198 patients from 2014 to 2019. Treatment groups included 153 attacks given high-dose intravenous steroids (HD-S), 14 given IVIG, 69 episodes of IVIG plus HD-S and 7 treated with plasma exchange. The proportion of patients with better outcomes were significantly lower in IVIG alone group than HD-S alone group (p = 0.004). However, sequential treatments for IVIG and HD-S yielded a higher likelihood of clinical improvement in severe attacks with EDSS ≥ 6.5 (OR = 5.85, p = 0.007). Conclusion These results did not support IVIG-alone therapy as a first-line option for acute NMOSD. However, adding HD-S to IVIG therapy was superior to HD-S alone for patients with high-onset EDSS.

Many studies have shown that LPS mainly activates four signal transduction pathways to induce inflammation, namely the p38, ERK1/2, JNK and IKK/NF-κB pathways. Studies have demonstrated that 5'-AMP-induced hypothermia (AIH) exhibits high anti-inflammatory capabilities. In this study, we explore that how AIH inhibits the inflammatory response. Wistar rats were divided into five groups: a control group, an LPS group, a 5'-AMP pre-treatment group, a 5'-AMP post-treatment group and a 5'-AMP group. For each group, plasma and lung were collected from the rats at 6h and 12h after LPS injection. ELISA assays were used to detect plasma levels of CD14, CRP and MCP-1. Inflammatory pathway activation and TLR4 expression were assayed separately by Western blot analysis and immunohistochemistry. Our results showed that rats treated with AIH either before or after an LPS-challenge had a significant decrease in plasma levels of CD14, CRP and TLR4 compared with rats that received LPS only. Western blot analysis showed that AIH inhibited the activation of extracellular signal-regulated kinases (ERK) 1/2, p38, c-Jun N-terminal kinase (JNK) and NF-κB in inflammatory rats. Our study concluded that AIH attenuated LPS-induced inflammation mainly by inhibiting activation on the ERK1/2, p38, JNK and NF-κB signaling pathways.

To identify the genetic determinants of colon tumorigenesis, 268 male mice from 33 inbred strains derived from different genealogies were treated with azoxymethane (AOM; 10 mg/kg) once a week for six weeks to induce colon tumors. Tumors were localized exclusively within the distal colon in each of the strains examined. Inbred mouse strains exhibit a large variability in genetic susceptibility to AOM-induced colon tumorigenesis. The mean colon tumor multiplicity ranged from 0 to 38.6 (mean = 6.5 ± 8.6) and tumor volume ranged from 0 to 706.5 mm3 (mean = 87.4 ± 181.9) at 24 weeks after the first dose of AOM. AOM-induced colon tumor phenotypes are highly heritable in inbred mice, and 68.8% and 71.3% of total phenotypic variation in colon tumor multiplicity and tumor volume, respectively, are attributable to strain-dependent genetic background. Using 97,854 single-nucleotide polymorphisms, we carried out a genome-wide association study (GWAS) of AOM-induced colon tumorigenesis and identified a novel susceptibility locus on chromosome 15 (rs32359607, P = 6.31 × 10–6). Subsequent fine mapping confirmed five (Scc3, Scc2, Scc12, Scc8, and Ccs1) of 16 linkage regions previously found to be associated with colon tumor susceptibility. These five loci were refined to less than 1 Mb genomic regions of interest. Major candidates in these loci are Sema5a, Fmn2, Grem2, Fap, Gsg1l, Xpo6, Rabep2, Eif3c, Unc5d, and Gpr65. In particular, the refined Scc3 locus shows high concordance with the human GWAS locus that underlies hereditary mixed polyposis syndrome. These findings increase our understanding of the complex genetics of colon tumorigenesis, and provide important insights into the pathways of colorectal cancer development and might ultimately lead to more effective individually targeted cancer prevention strategies. Mol Cancer Res; 10(1); 66–74. ©2011 AACR.

Commercial grade weakly basic resin D301 was impregnated with iron through a simple method using ferric chloride as the precursor for removing of 2-naphthalenesulfonic acid (2-NSA) from aqueous sol...

Purpose: We have previously mapped a major susceptibility locus influencing familial lung cancer risk to chromosome 6q23-25. However, the causal gene at this locus remains undeter- mined. In this study, we further refined this locus to identify a single candidate gene, by fine mapping using microsatellite markers and association studies using high-density single nucleotide polymorphisms (SNP). Experimental Design: Six multigenerational families with five or more affected members were chosen for fine-mapping the 6q linkage region using microsatellite markers. For association mapping, we genotyped 24 6q-linked cases and 72 unrelated noncancer controls from the Genetic Epidemiology ofLung Cancer Consortium resources using the Affymetrix 500K chipset. Significant associations were validated in two independent familial lung cancer populations: 226 familial lung cases and 313 controls from the Genetic Epidemiology of Lung Cancer Consortium, and154 familial cases and 325 controls from Mayo Clinic. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members. Results: A region-wide scan across 6q23-25 found significant association between lung cancer susceptibility and three single nucleotide polymorphisms in the first intron of the RGS17 gene. This association was further confirmed in two independent familial lung cancer populations. By quantitative real-time PCR analysis ofmatched tumor and normal human tissues, we f that RGS17 transcript accumulation is highly and consistently increased in sporadic lung cancers. Human lung tumor cell proliferation and tumorigenesis in nude mice are inhibited upon knockdown of RGS17 levels. Conclusion: RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25. Lung cancer can occur sporadically in people with no known family history of lung cancer or it can be familial, occurring in multiple members of the same family. Initial evidence of a genetic basis for susceptibility to lung cancer came from

Mice with a germ line p53 mutation (p53Ala135Val/wt) display increased susceptibility to lung, skin, and colon carcinogenesis. Here, we show that p53Ala135Val/wt mice developed ovarian tumors significantly more rapidly than their wild-type littermates after 7,12-dimethylbenz(a)anthracene (DMBA) treatment. Approximately 50% of the ovarian tumors in p53wt/wt mice and 23% in p53Ala135Val/wt mice are adenocarcinomas and the remaining tumors were adenocarcinoma mixed with sarcoma or ovarian sarcomas. All of the p53Ala135Val/wt mice had died of ovarian tumors 25 weeks after the initial DMBA treatment, whereas >50% of p53wt/wt mice were still alive. These mice not only have a shortened tumor latency but also closely resemble a subset of human ovarian tumors containing the p53 mutation. Microarray and GenMAPP analyses revealed that the mutant p53 (Ala135Val) affected several cellular processes, including the cell cycle, apoptosis, and Wnt pathways. These findings indicate that a germ line p53 mutation significantly enhanced DMBA-induced ovarian tumor development and progression. (Mol Cancer Res 2008;6(1):99–109)

In this study, we observed loss of heterozygosity (LOH) in human chromosomal fragment 6q25.1 in sporadic lung cancer patients. LOH was observed in 65% of the 26 lung tumors examined and was narrowed down to a 2.2-Mb region. Single-nucleotide polymorphism (SNP) analysis of genes located within this region identified a candidate gene, termed p34. This gene, also designated as ZC3H12D, C6orf95, FLJ46041, or dJ281H8.1, carries an A/G nonsynonymous SNP at codon 106, which alters the amino acid from lysine to arginine. Nearly 73% of heterozygous lung cancer tissues with LOH and the A/G SNP also exhibited loss of the A allele. In vitro clonogenic and in vivo nude mouse studies showed that overexpression of the A allele exerts tumor suppressor function compared with the G allele. p34 is located within a recently mapped human lung cancer susceptibility locus, and association of the p34 A/G SNP was tested among these families. No significant association between the less frequent G allele and lung cancer susceptibility was found. Our results suggest that p34 may be a novel tumor suppressor gene involved in sporadic lung cancer but it seems not to be the candidate familial lung cancer susceptibility gene linked to chromosomal region 6q23-25. [Cancer Res 2007;67(1):93–9]

Recent studies demonstrated that cholecystokinin (CCK) at physiological levels stimulates pancreatic enzyme secretion via a capsaicin-sensitive afferent vagal pathway. This study examined whether chemical ablation of afferent vagal fibers influences pancreatic growth and secretion in rats. Bilateral subdiaphragmatic vagal trunks were exposed, and capsaicin solution was applied. Pancreatic wet weight and pancreatic secretion and growth in response to endogenous and exogenous CCK were examined 7 days after capsaicin treatment. Perivagal application of capsaicin increased plasma CCK levels and significantly increased pancreatic wet weight compared with those in the control rats. Oral administration of CCK-1 receptor antagonist loxiglumide prevented the increase in pancreatic wet weight after capsaicin treatment. In addition, continuous intraduodenal infusion of trypsin prevented the increase in plasma CCK levels and pancreatic wet weight after capsaicin treatment. There were no significant differences in the expression levels of CCK-1 receptor mRNA and protein in the pancreas in capsaicin-treated and control rats. Intraduodenal administration of camostat or intravenous infusion of CCK-8 stimulated pancreatic secretion in control rats but not in capsaicin-treated rats. In contrast, repeated oral administrations of camostat or intraperitoneal injections of CCK-8 significantly increased pancreatic wet weight in both capsaicin-treated and control rats. Present results suggest that perivagal application of capsaicin stimulates pancreatic growth via an increase in endogenous CCK and that exogenous and endogenous CCK stimulate pancreatic growth not via vagal afferent fibers but directly in rats.

INTRODUCTION AND AIM Recent studies have suggested that CCK is not essential for normal pancreatic growth in mice. We examined whether the treatment of hyperglycemia participates in a non-CCK-1-receptor-mediated mechanism of pancreatic regeneration after partial (30%) pancreatectomy (Px) with use of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model for type 2 diabetes mellitus without CCK-1 receptor gene expression. METHODOLOGY Male OLETF rats were divided into five groups at 24 weeks of age. The first group was killed to examine the pancreas at 24 weeks of age (PrePx). The second group underwent a midline laparotomy and received a standard rat chow (ShamPx). The remaining three groups of rats received one of the following three treatments after Px: a standard rat chow (PxC), a diet containing acarbose (PxA), or a standard rat chow and once-daily subcutaneous injection of insulin (PxI) for 8 weeks. RESULTS PxC rats had significantly higher serum glucose levels than did PxA and PxI rats. Pancreatic weight and pancreatic contents of protein in PxA and PxI rats were significantly higher than in PxC rats. The pancreas in PxC rats was atrophic, and marked inflammatory cell infiltration was observed in the pancreas. In addition, tumor necrosis factor-alpha (TNFalpha) was expressed in the inflammatory cells, acinar cells, and islets in PxC rats. However, histologic alterations, including expression of TNFalpha, remained at a minimum in PxA and PxI rats. CONCLUSION We conclude that the control of serum glucose levels plays an important role in preventing pancreatic atrophy and participates in the non-CCK-1-receptor-mediated mechanisms of pancreatic growth in rats.

Tinnitus is the most common medical symptom that can be debilitating. Chinese herbal medicines (CHMs) play important roles in tinnitus treatment. This study analyzed the most frequently prescribed herbs used to treat tinnitus and the molecular mechanisms of therapeutic effects of these CHMs by text mining and bioinformatics technique. Results showed that pinellia ternate (Banxia) and gastrodin (Tianma) are the most frequently prescribed CHMs for treatment tinnitus. The molecular mechanisms of therapeutic effects of two CHMs were focused on sertoli cell-sertoli cell juntion signaling and NRF2-mediated oxidative stress response signaling. Integrative text mining and bioinformatics analysis may be a promising approach to find new drug and decipher their molecular mechanism intuitively.

Mammary gland hyperplasia (MGH) is a kind of endocrine disorder diseases, which is usually characterized by lump and pain in breast and an increased risk event of breast cancer. The complementary therapies of Traditional Chinese Medicine (TCM) play important roles in MGH treatment. This study analyzed the application of the TCM external therapy and food therapy by text mining. Subsequently, suitable techniques and methods which were frequently used on MGH treatment were explored. Results showed that external application of Chinese herb medicine, acupuncture, massage, catgut embedding, and magnet therapy were the top 5 TCM external therapy techniques, while fritillaria Oyster, alga, trionyx, kelp, arrowhead, pseudo-ginseng, lemon, leonurus, and hawthorn were the top 10 foods used for MGH treatment. The combinations of external therapy techniques were demonstrated in network, so does the combinations of the foods. The results provided good references for both clinical practice and basic research.

Acupoint application therapy is one of the Traditional Chinese medicine (TCM) external therapies, which has been used for coronary heart disease (CHD) treatment for a long time. The prescription of acupoint application therapy includes both Chinese herbal medicines (CHMs) and acupoints. This study aims to reveal the basic rules of acupoint selection in acupoint application therapy on CHD treatment by text mining study. Results showed that on CHD treatment, the most frequently used acupoint was Danzhong (RN17), followed by Xinshu (BL15), Neiguan (PC6), Zusanli (ST36) and Zhiyang (DU9). Acupoints closing to the heart or with specific functions were more frequently used. Moreover, Xinshu, Danzhong and Neiguan were of the top 3 relationships with other acupoints, while Zusanli and Sanyinjiao (SP6) were in the lower grade. The combination of Xinshu-Danzhong-Neiguan could be regard as the basic acupoint prescription of acupoint application therapy on CHD.

Hypertension becomes a major public health problem due to its high prevalence and serious complications. The complementary therapies of Traditional Chinese Medicine (TCM) play important roles in hypertension treatment. This study analyzed the application of the TCM external therapy and food therapy by text mining. Subsequently, suitable techniques and methods which were frequently used on hypertension treatment were explored. The text mining results showed that acupuncture, massage, Tuina, auricular-plaster and external application of Chinese herb medicine(CHM) were the top 5 TCM external therapy techniques, while placenta, lily root, pseudo-ginseng, peanut, sea horse, wine, radix aconiti carmichaeli, lemon, soybean and fructus crataegi were the top 10 foods used for hypertension treatment. The combinations of external therapy techniques were demonstrated in network, so does the combinations of the foods. The results provided good references for both clinical practice and medical research.

AIM: To examine the effects of pancreatic rest, stimulation and rest/stimulation on the natural course of recovery after acute pancreatitis. METHODS: Acute hemorrhagic pancreatitis (AP) was induced in male rats by intraductal infusion of 40 μL/100 g body weight of 3% sodium taurocholate. All rats took food ad libitum. At 24 h after induction of AP, rats were divided into four groups: control (AP-C), pancreas rest (AP-R), stimulation (AP-S), and rest/stimulation (AP-R/S). Rats in the AP-C, AP-R and AP-S groups received oral administration of 2 mL/kg body weight saline, cholecystokinin (CCK)-1 receptor antagonist, and endogenous CCK release stimulant, respectively, twice daily for 10 d, while those in the AP-R/S group received twice daily CCK-1 receptor antagonist for the first 5 d followed by twice daily CCK release stimulant for 5 d. Rats without any treatment were used as control group (Control). Biochemical and histological changes in the pancreas, and secretory function were evaluated on day 12 at 24 h after the last treatment. RESULTS: Feeding ad libitum (AP-C) delayed biochemical, histological and functional recovery from AP. In AP-C rats, bombesin-stimulated pancreatic secretory function and HOMA-β-cell score were significantly lower than those in other groups of rats. In AP-R rats, protein per DNA ratio and pancreatic exocrine secretory function were significantly low compared with those in Control rats. In AP-S and AP-R/S rats, the above parameters recovered to the Control levels. Bombesin-stimulated pancreatic exocrine response in AP-R/S rats was higher than in AP-S rats and almost returned to control levels. In the pancreas of AP-C rats, destruction of pancreatic acini, marked infiltration of inflammatory cells, and strong expression of α-smooth muscle actin, tumor necrosis factor-α and interleukin-1β were seen. Pancreatic rest reversed these histological alterations, but not atrophy of pancreatic acini and mild infiltration of inflammatory cells. In AP-S and AP-R/S rats, the pancreas showed almost normal architecture. CONCLUSION: The favorable treatment strategy for AP is to keep the pancreas at rest during an early stage followed by pancreatic stimulation by promoting endogenous CCK release.

Background Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of type 2 diabetes, lacks the expression of cholecystokinin-1 receptor mRNA and exhibits inflammation and degeneration of the pancreas and eventually develops insulinopenic diabetes. Protease inhibitors are known to modulate inflammatory response and fibrosis as well as inhibit proteases activity. Aim To examine the effects of long-term treatment with camostat, a synthetic protease inhibitor, on metabolic and histopathological changes in the islets of OLETF rats. Method OLETF rats were fed either camostat-containing food (200 mg/100 g) from 12 or 28 weeks of age to 72 weeks of age, or fed standard rat diet. Results Camostat-fed rats gained less weight or lost weight, although they consumed more food than the control rat when food intake was adjusted for body weight. Camostat reduced visceral adipose depots and fasting serum concentrations of triglyceride, free fatty acids, cholesterol, glucose, and insulin. Pancreatic insulin content in camostat-treated rats was significantly higher than in control rats. Immunohistochemistry revealed marked suppression of expressions of tumor necrosis factor α , interleukin 1 β , interleukin 6, and α -smooth muscle actin in the islets of camostat-treated rats, compared with control rats. Histologically, disruption of the islets and pancreatic fibrosis were noted in control rats but not in camostat-fed rats. Conclusion Our findings suggest that camostat prevents and reverses obesity, hyperinsulinemia, hyperglycemia, and hyperlipidemia and markedly inhibits inflammation, fibrosis, and disruption of the islets in the genetically obese diabetic OLETF rats.

Type 2 diabetes is caused by insulin resistance and beta-cell dysfunction. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an established animal model of human type 2 diabetes that exhibits chronic and slowly progressive hyperglycemia and hyperlipidemia and is accompanied by progressive fibrosis in the islets. The aim of the present study was to examine whether worsening of hyperglycemia, insulin resistance, and histologic alterations of the islets in OLETF rats is related to hyperlipidemia by treating these animals with a lipid-lowering drug, bezafibrate. The bezafibrate-treated groups of OLETF and their control counterpart Long-Evans Tokushima Otsuka (LETO) rats received a bezafibrate-rich diet (150 mg/100 g normal chow) for 16 weeks, from 12 to 28 weeks of age, while the other groups of rats received standard rat chow. Bezafibrate treatment significantly reduced serum triglyceride (TG) and free fatty acid (FFA) levels, suppressed the increase in islet size, and inhibited the expression of alpha-smooth muscle actin, a marker for activated pancreatic stellate cells that are involved in the fibrosis of the pancreas, in the islets in OLETF rats, but had no influences on food intake, body weight gain, abdominal adipose depots, and pancreatic insulin content in both strains of rats. Although bezafibrate significantly reduced circulating lipid levels and suppressed the increase in insulin secretion evaluated by area under the curve (AUC) analysis in response to an intravenous glucose tolerance test (IVGTT) until the end of the experiment, improvement of insulin resistance was observed only for the first 8 weeks after the onset of bezafibrate treatment. These results suggest that dyslipidemia is not responsible for the reduced insulin sensitivity, but the impairment of glucose tolerance is the primary defect in the OLETF rats, although improvement of dyslipidemia suppressed histologic alterations in the islets and temporally improved insulin resistance.

Damage to the exocrine pancreas has been observed in patients and animals with hyperlipidemia and hyperglycemia. Bezafibrate, a peroxisome proliferator-activated receptor (PPAR)-alpha activator, has been shown to improve lipid and glucose metabolism, and to interfere with the inflammatory response.To examine the effects of bezafibrate on exocrine pancreas in hyperlipidemic obese and diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats that have no cholecystokinin-1 receptor gene expression.One group of rats (n = 8) received a bezafibrate-rich diet (150 mg/100 g normal chow) from 12 weeks of age until 30 weeks of age, whereas a control group (n = 8) received standard rat chow.Bezafibrate treatment significantly reduced serum triglyceride, total cholesterol, and free fatty acids levels and significantly increased the pancreatic wet weight (1,145 +/- 54 vs 874 +/- 33 mg/rat, p0.01), and protein (169 +/- 7 vs 128 +/- 11 mg/pancreas p0.01) and enzyme contents in the pancreas compared with those in untreated control rats. Immunohistochemical studies of the pancreas showed that expression of proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1beta and interleukin-6, and alpha-smooth muscle actin in bezafibrate-treated rats was greatly suppressed compared with that in the untreated control rats. The histopathologic changes such as vacuolar degeneration and tubular complexes observed in the control rat pancreas were markedly improved in bezafibrate-treated rats.Our results suggest that bezafibrate reduces hyperlipidemia, inhibits pancreatic inflammation, and prevents pancreatic degeneration in obese and diabetic OLETF rats.