Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

Background Silicosis is a diffuse fibrosis of the lungs caused by long-term inhalation of free silicon dioxide (SiO₂). It has a complex pathogenesis and lacks effective treatment. Brusatol (Bru) has a variety of biological activities, and its role in silicosis fibrosis is unclear yet. Objective To investigate the effects of different concentrations of Bru on SiO₂-induced silicosis fibrosis in mice. Methods Thirty male C57BL/6J mice were randomly divided into five groups: a control group, a silica group, and three Bru intervention groups with low, medium, and high doses (1, 2, and 4 mg·kg⁻¹), with 6 mice in each group. Except the control group, the remaining groups were established as SiO₂-induced silicosis mouse models by using a single tracheal infusion of 50 μL 60 mg·mL⁻¹ SiO₂ suspension. The control group was dosed with equal amount of saline. The Bru intervention groups were injected intraperitoneally with Bru for 5 consecutive days and then injected every other day. After 28 d of exposure, the mice were executed and lung tissues were collected. The lung coefficient of the mice was measured, and the pathological changes of the lung tissues were observed after hematoxylin-eosin (HE) and Masson staining. The levels of apoptotic protein Cleaved-caspase 3, fibrosis-related protein α-smooth muscle actin (α-SMA), type I collagen (Col-I), autophagy-associated protein Beclin1, microtubule-associated protein 1 light chain 3 (LC3), Sequestosome 1 (p62/SQSTM1), Kelch like ECH-associated protein-1 (Keap1), and nuclear factor erythroid 2 related factor 2 (Nrf2) were detected by Western blot. The mRNA levels of Caspase 3, α-SMA, and Col-I were measured by realtime fluorescence-based quantitative PCR. Results Compared with the control group, the lung coefficient of mice in the silica group was significantly increased (P < 0.01); the lung tissues of the silicosis mice showed damaged alveolar walls, along with infiltration of inflammatory cells, fibrous nodules, and collagen deposition; furthermore, the protein and mRNA levels of Cleaved-caspase 3, α-SMA, and Col-I were significantly increased (P < 0.01); the expression levels of Beclin1, LC3-II/I, p62, and Nrf2 were increased, while that of Keap1 was decreased (P < 0.05). The interventions with low and medium doses of Bru reduced lung coefficient (P < 0.05) and protected against pathological damage and collagen deposition in the lung tissues of the silicosis mice; the protein and mRNA expression levels of Cleaved-caspase 3, α-SMA, and Col-I were significantly decreased in the low and medium dose groups (P < 0.05, P < 0.01), the expression levels of Beclin1, LC3-II/I, p62, and Nrf2 were also decreased (P < 0.05, P < 0.01), and the expression level of Keap1 was increased in the medium dose group (P < 0.05). However, compared with the silica group, the differences in lung coefficient, pathological damage, and protein and mRNA expression levels of Cleaved-caspase 3, α-SMA, and Col-I in the Bru high dose group were not statistically significant (P > 0.05). In addition, the high dose of Bru decreased Beclin1, LC3-II/I, and Nrf2 expression levels (P < 0.01), did not change p62 protein expression level (P > 0.05), while increased Keap1 protein level (P < 0.01). Conclusion Low and medium doses of Bru might regulate autophagy through the Keap1-Nrf2 pathway, ameliorate autophagic degradation impairment, reduce pulmonary coefficient, attenuate apoptosis, and delay the progression of fibrosis in SiO₂-induced silicosis mice.

Objective:To analyze the changes in the disease burden of prostate,testis,kidney and bladder cancers among uri-nary and reproductive system tumors in Chinese men from 1990 to 2019 with a prediction of the future trend.Methods:We re-trieved the data on the incidence,mortality and disease burden of prostate,testis,kidney and bladder cancers in Chinese men between 1990 and 2019 from the database of Global Burden of Disease Study 2019.Using the Joinpoint regression model,we analyzed the trend of changes in the disease burden,and predicted the prevalence of the tumors with the ARIMA model.Results:From 1990 to 2019,the standardized incidence and prevalence of prostate,testis,kidney and bladder cancers were on the rise in Chinese men,and those of testis cancer increased most significantly,by 326.79% and 1070.93% respectively.The disease burden of PCa was the highest,with standardized incidence,prevalence and mortality ratios of 17.34/100 000,117.65/100 000 and 7.79/100 000 respectively in 2019.The standardized mortality and disability-adjusted life years(DALY)of kidney cancer were increased by 103.59% and 103.17% respectively.The highest incidence,mortality and DALY of prostate,kidney and bladder cancers in 2019 were found in 90-94 years old males,the highest prevalence rates of prostate,kidney and bladder cancers in the 70-89-year-olds,and the highest prevalence of testis cancer in the25-49-year-olds.ARIMA model prediction showed that the standardized incidence rates of prostate,testis,kidney and bladder cancers in Chinese men kept rising from 2020 to 2029.Conclusion:The disease burden of prostate,tes-tis,kidney and bladder cancers in Chinese men is on the rise,and their standardized incidence rates will be even higher by 2029,with a significant increase in the disease burden in young men,which suggests the need of more attention to the prevention and treatment of genitourinary system tumors in young males.

Tweety-homolog 1 (Ttyh1) is expressed in neural tissue and has been implicated in the generation of several brain diseases. However, its functional significance in pain processing is not understood. By disrupting the gene encoding Ttyh1, we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice, along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) in the basal state. More importantly, the peripheral inflammation-evoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice. Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release. Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief. Thus, in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.

Objective:The aim of this study is to establish an evaluation framework for an integrated health care service system,which provides evidence for the further construction of the evaluation index system. Methods:A sys-tematic review,thematic system and expert consultation were synthetically used to screen,construct and improve the evaluation framework of the integrated health care service system. Results:The results of this study show that the fi-nalized evaluation framework of the integrated health care system contains 4 first-level indexes which include system integration,organizational integration,professional integration and service integration; and 25 corresponding second level indictors. Conclusions:The evaluation framework of the integrated health care service system constructed in this study has a strong effectiveness and suitability, which lays a good foundation for further development of the corre-sponding evaluation index system.

Objective: To investigate the changes of proportion on both consistent condom use and syphilis infection among low-fee female sex workers aged 35 and above (LFSW), in order to provide evidence for targeted intervention strategies. Methods: A total of six cities-Liuzhou city and Pingnan couty of Guigang city of Guangxi Zhuang Autonomous Region, Jinghong city of Xishuangbanna Dai autonomous prefecture and Dali city of Dali Bai autonomous prefecture of Yunnan province, Zhangjiajie city and Jianghua Yao autonomous county of Yongzhou city Hunan province were involved in this study, with 60 eligible participants needed in each city, estimated through a pre-study. The first cross-sectional survey was completed from October 2012 to January 2013. Face-to-face questionnaire interview was carried out to collect information on socio-demography, work-related information and condom use situation. Blood was collected for syphilis testing. The second cross-sectional survey was carried out from June to September, 2015 under the same procedure. Results: A total of 371 and 403 eligible participants were included in the first and second survey, respectively. When comparing the two surveys, we noticed that the average age showed a slight change, from 42.4 years to 43.8 years old (t=3.537, P<0.001) and the average price for every commercial sex exchange increased from 36.8 RMB to 49.5 RMB (t=11.961, P<0.001). In the first survey, 46.9% (174/371) of the participants had more than two years of experience working as LFSW, compared to 61.3% (247/403) in the second survey (χ(2)=16.125, P<0.001). Also, 46.9% (174/371) of the participants consistently used condoms with clients in the past month in the first survey versus 64.3% (259/403) (χ(2)=23.641, P<0.001) in the second one. Rates of syphilis infection were found from 15.9% (59/371) in the first survey reduced to 7.2% (29/403) in the second survey (χ(2)=14.533, P<0.001). Conclusion: Compared with the first survey, the proportion of consistent condoms use showed an increase. Although the proportion of syphilis infection decreased in the second survey, the scope did not meet the criteria on syphilis, set by the government. Targeted intervention strategies on condom promotion and syphilis control should be implemented consistently in this population.
Adult ; China/epidemiology* ; Condoms/trends* ; Cross-Sectional Studies ; Female ; Humans ; Prevalence ; Risk Factors ; Safe Sex ; Sex Work ; Sex Workers ; Sexually Transmitted Diseases/epidemiology* ; Surveys and Questionnaires ; Syphilis/prevention & control* ; Syphilis Serodiagnosis

Through an introduction to the importance of medical ethics education and the status quo, this paper discusses how to better combine the medical ethics education with medical students′medical practices. It puts for-ward some suggestions from the institutional arrangements, personnel allocation, and publicitymethods. The ulti-mate goal is that the medical students could get more effective, continue and integration medical ethics education in the process of medical practice.

Objective To investigate the value of 18F-FDG PET-CT in detection and accurate staging of extranodal non-Hodgkin lymphoma (NHL).Methods The results of PET-CT of 94 patients with NHL were retrospectively analyzed.The consistency of checking out lesions and accurate staging by PET-CT were compared with those by other imaging examination in extranodal NHL.Results 432 lesions were checked out by PET-CT, including 319 (73.8 ％) lymphoid tissues and organs with the average SUVmax of 13.4 (3.4-33.4), and 113 (26.2 ％) extranodal lesions with the average SUVmax of 13.5 (3.1-55.0).The detection consistent rate between CT and PET-CT for lymphoid tissues and lymph organ lesions was 95 ％, while the consistent rate of the extranodal lesions was only 54.9 ％.The detection rates of PET-CT for soft tissue, bone and gastrointestinal lesions were higher than those of CT, but the detection rate for the bone marrow lesion was lower than that for the bone marrow cytology.According to the results of PET-CT, the stages of 29 patients (31.0 ％) were re-adjusted, including up-regulated for 75.9 ％ (22/29) because of high detection rates of PET-CT for soft tissue and skeletal lesions, and down-regulated for 24.1％ (7/29) mainly due to the strong resolution capability of PET-CT for detection of non-neoplastic lymph nodes and spleen increasing or effusion.Conclusion 18F-FDG PET-CT can improve the detection rate of NHL extranodal lesions, especially for diffuse non-mass lesions in bone and soft tissues, which facilitates the accurate lymphoma staging.

OBJECTIVETo explore the prognostic factors for very severe aplastic anemia (VSAA) patients treated mainly with Chinese Kidney (Shen)-invigorating drugs (CKID) combined with anti-lymphocyte globulin (ALG) or anti-thymocyte globulin (ATG).

METHODSTwenty-seven VSAA patients were treated with CSID+ALG/ATG therapy in conjunction with cyclosporine A, androgen, hemopoietic growth factor, etc. The relationship of the effectiveness and some factors (age of patients, course of illness, blood and bone marrow figures, etc.) were analyzed.

RESULTSIn the 25 evaluated VSAA patients who had been followed up for over 1 year, 9 patients (36.0%) were basically cured, 5 (20.0%) remitted, 6 (24.0%) were markedly improved, and 5 (20.0%) were treated in vain, with the total effective rate of treatment being 80.0% (20/25). Better clinical therapeutic effects were shown in patients newly diagnosed with VSAA, of male sex (P=0.037), >20 years old (P=0.045), with an illness course [Symbol: see text] month (P=0.048), with peripheral neutrophil count >0.1 × 10(9)/L (P=0.023), and with reticulocyte count >10 × 10(9)/L (P=0.002). Platelet count (P=0.620) and bone marrow lymphocyte percentage (P=0.736) showed no correlation with the therapeutic effectiveness. Multi-factor analysis by the Kaplan-Meier procedure on the factors influencing survival showed that rather longer survival times occurred in patients > 20 years old, with peripheral neutrophil count [Symbol: see text] 0.1 × 10(9)/L, reticulocyte count [Symbol: see text]10 × 10(9)/L, and platelet count > 10 × 10(9)/L (all P=0.0001). Bone marrow lymphocyte percentage and the initiation time of ALG/ATG application (from onset of the illness) showed no significant influence on patients' survival time (P=0.085 and P=0.935, respectively).

CONCLUSIONSCSKD+ALG/ATG therapy for treatment of VSAA could enhance the current clinical therapeutic effects and elevate patients' survival rate. Conditions including male sex, age >20 years, illness course [Symbol: see text]1 month, neutrophil count >0.1 × 10(9)/L, and reticulocyte count >10 × 10(9)/L are the likely effective indices for predicting favorable therapeutic effectiveness in newly diagnosed VSAA patients.

Adolescent ; Adult ; Anemia, Aplastic ; diagnosis ; drug therapy ; pathology ; Animals ; Antilymphocyte Serum ; pharmacology ; therapeutic use ; Child ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; Horses ; Humans ; Kidney ; drug effects ; Male ; Middle Aged ; Prognosis ; Survival Analysis ; Sus scrofa ; Time Factors ; Treatment Outcome ; Young Adult

Objective To investigate the effect of dysfunction of T lymphocytes on clonal haematogenesis in patients with myelodysplastic syndrome (MDS). Methods The cytogentics, the subsets of lymphocytes and their activation in 76 patients with MDS were analyzed. Results There were 36 patients with normal karyotype and 40 patients with abnormal karyotype. The incidence of abnormal karyotype were 52.6 %. There were 24 cases (60.0 %) with trisomy 8 (+8) in 40 cases of abnormal karyotype. The expression rates of CD+3 CD-19 cells, CD+3 CD-4 CD+8 cells and CD+3 HLA-DR+ cells in MDS were significantly increased, and CD-3 (CD16CD56)+ cells were significantly lower than that in control group. The expression rates of CD+3 (CD16CD56)+ cells in MDS with abnormal karyotype were significantly higher than that in control group. The expression rates of CD+3 CD+4 CD-8 cells in +8 MDS were significantly lower than that in MDS patients with normal karyotype and with other abnormal karyotype. The ratio of CD4/CD8 in +8 MDS were significantly lower than that in control group. Conclusion The abnormalities of T cell subsets and functions in patients with MDS were observed and the proliferation of malignant clone was prevalent which indicated a poor prognosis in MDS with abnormal karyotype. Dysfunction of immunosurveillance was more aggravated in +8 MDS, which led to excess proliferation of malignant clone and over inhibition of remaining haematogenesis.