CAD Modeling method of the electrospun membrane under multifractal dimension optimization control.

Based on an analysis of large sample data, this paper improves the calculation method of the fractal dimension in an electrospun membrane and proposes a method to generate a computer-aided design (CAD) model of an electrospun membrane under the control of fractal dimension. Fifteen electrospun membrane samples of PMMA and PMMA/poly(vinylidene fluoride) (PVDF) materials were prepared under similar concentrations and voltage parameters, and 525 SEM images of the surface morphology with a resolution of 2560 × 1920 were taken as a dataset. The feature parameters, such as fiber diameter and direction, are extracted from the image. Second, based on the minimum value of the power law behavior, the pore perimeter data were preprocessed to calculate the fractal dimensions. A 2D model was reconstructed randomly based on the inverse transformation of the characteristic parameters. The genetic optimization algorithm adjusts the fiber arrangement to realize the control of characteristic parameters, such as the fractal dimension. Based on the 2D model, a long fiber network layer with a thickness consistent with the depth of the SEM shooting is generated in ABAQUS software. Finally, a solid CAD model of the electrospun membrane with realistic thickness was constructed by combining multiple fiber layers. The result shows that the improved fractal dimension exhibits multifractal characteristics and distinct sample differences, which are more similar to the experimental results. The proposed 2D modeling method of the long fiber network can allow the control of various characteristic parameters, including the fractal dimension, and can generate the required model quickly.

Continuation, reduction, or withdrawal of tofacitinib in patients with rheumatoid arthritis achieving sustained disease control: a multicenter, open-label, randomized controlled trial / 中华医学杂志(英文版)

BACKGROUND@#Rheumatoid arthritis (RA), a chronic systemic autoimmune disease, is characterized by synovitis and progressive damage to the bone and cartilage of the joints, leading to disability and reduced quality of life. This study was a randomized clinical trial comparing the outcomes between withdrawal and dose reduction of tofacitinib in patients with RA who achieved sustained disease control.@*METHODS@#The study was designed as a multicenter, open-label, randomized controlled trial. Eligible patients who were taking tofacitinib (5 mg twice daily) and had achieved sustained RA remission or low disease activity (disease activity score in 28 joints [DAS28] ≤3.2) for at least 3 months were enrolled at six centers in Shanghai, China. Patients were randomly assigned (1:1:1) to one of three treatment groups: continuation of tofacitinib (5 mg twice daily); reduction in tofacitinib dose (5 mg daily); and withdrawal of tofacitinib. Efficacy and safety were assessed up to 6 months.@*RESULTS@#Overall, 122 eligible patients were enrolled, with 41 in the continuation group, 42 in the dose-reduction group, and 39 in the withdrawal group. After 6 months, the percentage of patients with a DAS28-erythrocyte sedimentation rate (ESR) of <3.2 was significantly lower in the withdrawal group than that in the reduction and continuation groups (20.5%, 64.3%, and 95.1%, respectively; P  < 0.0001 for both comparisons). The average flare-free time was 5.8 months for the continuation group, 4.7 months for the dose reduction group, and 2.4 months for the withdrawal group.@*CONCLUSION@#Withdrawal of tofacitinib in patients with RA with stable disease control resulted in a rapid and significant loss of efficacy, while standard or reduced doses of tofacitinib maintained a favorable state.@*TRIAL REGISTRATION@#Chictr.org, ChiCTR2000039799.

Prevalence of psoriatic arthritis in Chinese population with psoriasis: A multicenter study conducted by experienced rheumatologists / 中华医学杂志(英文版)

BACKGROUND@#Reports on the prevalence of psoriatic arthritis (PsA) among Chinese patients with psoriasis are very limited. This study, conducted by rheumatologists, estimated the prevalence of PsA in a large number of Chinese patients with psoriasis.@*METHODS@#Consecutive patients with a confirmed diagnosis of psoriasis attending nine dermatology clinics in five hospitals were recruited. All psoriasis patients were asked to complete a questionnaire comprising 16 questions to identify possible cases of PsA. All patients with one or more positive answers to the questionnaire were evaluated by two experienced rheumatologists.@*RESULTS@#A total of 2434 psoriasis patients, including 1561 males and 873 females, were enrolled. Both the questionnaire and rheumatologists' examinations were completed in the dermatology clinics. The results identified 252 patients with PsA, comprising 168 males and 84 females. The overall prevalence of PsA among psoriasis patients was 10.4% (95% confidence interval [95% CI], 9.1%-11.7%). By sex, the prevalence was 10.8% (95% CI, 9.2%-12.5%) for males and 9.6% (95% CI, 7.7%-11.9%) for females and there was no significant sex difference in the prevalence of PsA (P = 0.38). Of the 252 PsA patients, 125 (49.6%, 95% CI, 41.3%-59.1%) were newly diagnosed by rheumatologists. Consequently, the prevalence of undiagnosed PsA among psoriasis patients was 5.2% (95% CI, 4.4%-6.2%).@*CONCLUSION@#The prevalence of PsA in the Chinese population with psoriasis is about 10.4%, which is almost double that of previous reports in the Chinese population, but lower than that in Caucasians.

The mediating effect of resilience on anxiety and subjective well-being in occupational population / 中华劳动卫生职业病杂志

Objective: To explore the current situation of anxiety, subjective well-being in occupational population and the mediating effect of resilience. Methods: From March 24th to 26th, 2020, a cross-sectional survey was conducted among occupational population aged ≥18 years old using online questionnaires. A total of 2134 valid questionnaires were obtained, with respondents from 30 provinces, autonomous regions, and municipalities directly under the Central Government. Their general demographic data, subjective well-being, anxiety, and resilience were collected. Pearson χ(2) test and Spearson correlation analysis were used for data analysis, and structural equation model was used to explore the mediating effect of resilience on anxiety and subjective well-being. Results: The age of the respondents ranged from 18 to 60 years old, with an average age of (31.19±7.09) years old, including 1075 (50.4%) women and 1059 (49.6%) men. The positive rates of low subjective well-being and anxiety were 46.5% (992/2134) and 28.4% (607/2134), respectively. Anxiety scores were significantly negatively correlated with subjective well-being scores and resilience scores (r(s)=-0.52, -0.41, P<0.05), while resilience was significantly positively correlated with subjective well-being (r(s)=0.32, P<0.05). Structural equation models showed that anxiety had a negative predictive effect on subjective well-being, while resilience not only had a positive predictive effect on subjective well-being, but also played a mediating role between anxiety and subjective well-being, with a mediating effect of 9.9%. Conclusion: The situation of anxiety and well-being in the occupational population is still not optimistic, and resilience has a mediating effect between anxiety and subjective well-being.

Electroacupuncture at Siguan points for migraine of liver yang hyperactivity: a randomized controlled trial / 中国针灸

OBJECTIVE@#To compare the clinical effect of electroacupuncture at Siguan points and flunarizine hydrochloride capsule on migraine of liver yang hyperactivity.@*METHODS@#A total of 110 patients with migraine of liver yang hyperactivity were randomly divided into an electroacupuncture group (55 cases, 2 cases dropped off) and a western medication group (55 cases, 2 cases dropped off). In the electroacupuncture group, electroacupuncture was applied at Siguan points (Hegu [LI 4] and Taichong [LR 3]), with disperse-dense wave of 2 Hz/100 Hz in frequency and current intensity of 0.1-1 mA, 30 min each time, once a day, 5 times per week for 4 weeks. Flunarizine hydrochloride capsule was given orally in the western medication group, 10 mg a day for 4 weeks. The visual analogue scale (VAS) score and the migraine attack days were observed before and after treatment, during follow-up of 1, 3 and 6 months, and the migraine symptom score was observed before and after treatment in the two groups.@*RESULTS@#After treatment, during follow-up of 1, 3 and 6 months, the VAS scores and the migraine attack days in the two groups were decreased compared with before treatment (Ｐ<0.05), and above indexes in the electroacupuncture group were lower than the western medication group (Ｐ<0.05). After treatment, the migraine symptom scores in the two groups were decreased (Ｐ<0.05), the change in the electroacupuncture group was greater than the western medication group (Ｐ<0.05).@*CONCLUSION@#Electroacupuncture at Siguan points could effectively reduce headache intensity and migraine attack days, relieve migraine symptoms in patients with migraine of liver yang hyperactivity, and the efficacy is superior to oral flunarizine hydrochloride capsules.

Training doctors for people health: teaching preventive medicine for clinical medicine students in Fudan medical college / 上海预防医学

Preventive medicine is a required course for students majoring in clinical medicine, which is essential for them to understand public health. Teaching teams of Fudan University have focused on the curriculum reform of preventive medicine and kept innovating with the aim of improving the competence of future doctors. Flipped classroom approach was adopted to promote interaction between teachers and students. In addition, a variety of practice sectors were integrated into teaching process, such as diet calculation through graph cards, health risk appraisal practice, hospital visiting. In addition, a 4-weeks community-based practice further strengthened students' understandings of public health in the real world. Much attention was on cultivate scientific spirit, humanity and the capability to serve the people. A multi-dimension, whole-process evaluation is applied and the results shows that the students' comprehensive ability and literacy are significantly improved.

Effect of Dahuang Zhechong Pills combined with TACE on VEGF, MMP-2, TGF-β1 and immune function of patients with primary liver cancer (blood stasis and collaterals blocking type) / 中国中药杂志

To investigate the effects of Dahuang Zhechong Pills combined with hepatic arterial chemoembolization(TACE) on tumor index and immune function of patients with primary liver cancer(blood stasis and collaterals blocking type), observe its application values in treatment of such patients, and provide effective treatment means for this disease. From June 2019 to December 2019, 79 patients with confirmed primary liver cancer(blood stasis and collaterals blocking type) treated in Wenzhou Hospital of Traditional Chinese Medicine were included in this study, all of which were grouped with random number table method before inclusion in this study. 40 patients in the control group were treated with TACE, while 39 patients in the observation group were treated with Dahuang Zhechong Pills combined with TACE. The efficacy was compared between two groups after 4 weeks of treatment. The immune function indexes of serum CD4~+ cells, CD4~+/CD8~+, CD3~+ cells of the observation group were higher than those in control group after treatment(P<0.05), and tumor indexes such as serum alpha-fetoprotein(AFP), carbohydrate antigen 199(CA199) and glutamic-pyruvic transaminase(ALT), total bilirubin(TBiL) levels were lower than those in the control group, with statistically significant differences(P<0.05). Plasma vascular endothelial growth factor(VEGF), transforming growth factor-β1(TGF-β1), and matrix metalloprotei-nase-2(MMP-2) levels in the observation group were lower than those in the control group after treatment, with statistically significant differences(P<0.05). The total effective rate of the observation group was 87.18%, higher than 67.50% in the control group, and the benefit rate was 94.87% in the observation group, higher than 85.00% in the control group(P<0.05). The total incidence of adverse reactions such as bone marrow suppression, gastrointestinal reaction, fever, renal function injury and peripheral nerve injury in the observation group was 48.72%, lower than 82.50% in the control group, with statistically significant difference(P<0.05). In summary, the combination of Dahuang Zhechong Pills with TACE could improve immunity, protect liver function, and reduce the risk of metastasis and the incidence of adverse reactions from chemotherapy, so it is worth popularizing for patients with primary liver cancer(blood stasis and collaterals blocking type).

Changes of Anti-tuberculosis Herbs Formula During Past Three Decades in Contrast to Ancient Ones / 中国结合医学杂志

OBJECTIVE@#To investigate the evolution of herbal medicine in treating tuberculosis (TB) and encourage anti-TB drug discovery and development.@*METHODS@#In this study, 477 ancient traditional Chinese medicine formulae were collected from the Dictionary of Traditional Chinese Medicine Prescriptions and 172 modern Chinese medicine formulae (from 1986 to 2016) were collected by searching 4 databases: WanFang Data Knowledge Service Platform, China National Knowledge Infrastructure Database (CNKI), China Science and Technology Journal Database (VIP) and Chinese Bio-medical Literature and Retrieval System (SinoMed) in Chinese. We restricted the search to publications in Chinese. Further data analysis was done using the Traditional Chinese Medicine Inheritance Support System version 2 Software.@*RESULTS@#There were 425 herbs in the 477 ancient formulae and 257 herbs in the 172 modern formulae. Half of the top 30 herbs were shared by both modern and ancient prescriptions. They are Radix Ophiopogonis, Astragalus membranaceus, Fritillaria cirrhosa, Dried rehmannia glutinosa, Poria cocos, Angelica sinensis, Prepared rehmannia glutinosa, Platycodon Root, Radix paeoniae alba, Schisandra chinensis, Bighead atractylodes rhizome, Rhizoma anemarrhenae, Cortex lycii radicis and Radix Scutellariae. Only two groups of herbs with a high correlation coefficient were found in both modern and ancient prescriptions, the Dried rehmannia glutinosa with Radix ophiopogonis, and Radix ophiopogonis with Prepared rehmannia glutinosa. There were 9 and 15 core herb combinations in modern and ancient prescriptions, respectively, but no one was found simutaniously in both modern and ancient prescriptions.@*CONCLUSIONS@#Although there were wide variations in the herb groups and herb combinations in the formulae, half of the top 30 herbs were found in both modern and ancient prescriptions. The core herb combinations in modern and ancient prescriptions could help us to improve the priscription for treatment of TB.

Co-infection of influenza A virus enhances SARS-CoV-2 infectivity

The upcoming flu season in the northern hemisphere merging with the current COVID-19 pandemic raises a potentially severe threat to public health. Through experimental co-infection of IAV with either pseudotyped or SARS-CoV-2 live virus, we found that IAV pre-infection significantly promoted the infectivity of SARS-CoV-2 in a broad range of cell types. Remarkably, increased SARS-CoV-2 viral load and more severe lung damage were observed in mice co-infected with IAV in vivo. Moreover, such enhancement of SARS-CoV-2 infectivity was not seen with several other viruses probably due to a unique IAV segment as an inducer to elevate ACE2 expression. This study illustrates that IAV has a special nature to aggravate SARS-CoV-2 infection, and prevention of IAV is of great significance during the COVID-19 pandemic.

Risk factors for critical-ill events of patients with COVID-19 in Wuhan, China: a retrospective cohort study

BackgroundLittle is known about the risk factors for critical-ill events (intensive care, invasive ventilation, or death) in patients with COVID-19. MethodsPatients with laboratory-confirmed COVID-19 admitted to the Wuhan Leishenshan Hospital from February 13 to March 14 was retrospectively analyzed. Demographic data, symptoms, laboratory values at baseline, comorbidities, treatments and clinical outcomes were extracted from electronic medical records and compared between patients with and without critical-ill events. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression models were developed to explore the risk factors for critical-ill events. A risk nomogram was established to predict the probability for the critical-ill events. Survival analysis of patients with critical-ill events was performed by the Kaplan-Meier method. Results463 COVID-19 patients were included in this study, of whom 397 were non-critically ill and 66 were critically ill (all from the intensive care unit). The LASSO regression identified four variables (hypersensitive cardiac troponin I, blood urea nitrogen, haemoglobin, and interleukin-6) contributing to the critical-ill events. Multivariable regression showed increasing odds of in-hospital critical-ill events associated with hypersensitive cTnI greater than 0.04 ng/mL (OR 20.98,95% CI 3.51-125.31), blood urea nitrogen greater than 7.6 mmol/L (OR 5.22, 95% CI 1.52-17.81, decreased haemoglobin (OR 1.06, 95% CI 1.04-1.10), and higher interleukin-6 (OR 1.05, 95% CI 1.02-1.08) on admission. ConclusionsHypersensitive cTnI greater than 0.04 ng/mL, blood urea nitrogen greater than 7.6 mmol/L, decreased haemoglobin, and high IL-6 were risk factors of critical-ill events in patients with COVID-19. Main pointHypersensitive cTnI greater than 0.04 ng/mL, BUN greater than 7.6 mmol/L, decreased haemoglobin, and high IL-6 were risk factors of critical-ill events (intensive care, invasive ventilation, or death) in patients with COVID-19.

A novel treatment for psoriatic arthritis: Janus kinase inhibitors / 中华医学杂志(英文版)

Psoriatic arthritis (PsA) is a type of chronic inflammatory arthritis which is associated with psoriasis. The early recognition and treatment for PsA are of critical importance. Janus kinase (JAK) inhibitors, as a kind of orally small molecules, have emerged as an encouraging class of drug in PsA treatment. This review provides a discussion of the role and current status of JAK inhibitors in the control of PsA. There are three JAK inhibitors approved for use in autoimmune diseases, for example, tofacitinib, baricitinib, and upadacitinib, and only tofacitinib has been approved in PsA treatment. The clinical trials of upadacitinib and filgotinib in PsA patients are undergoing. The efficacy and safety of these agents were briefly discussed. Although there are still issues in terms of their efficacy and safety currently, JAK inhibitors are expected to benefit more PsA patients in future.

Perspectives on governance for health and Healthy City development / 上海预防医学

The paper highlights the three key words:city, health and development.On the one hand, it is necessary to understand the city with systematic thinking, to focus on the health gap and health equity of different populations in the same city, and the continuous spectrum of health indicators or disease distribution in the same population.On the other hand, it is suggested to establish a "participatory governance" model in Healthy City development-government for health, to further promote the development of healthy cities.Finally, it briefly introduces the report of "Healthy City 2.0-Towards a Planet City" presented by Professor Hancock at the 23rd International Conference on Health Promotion of IUHPE, 2019 in New Zealand.

Perspectives on governance for health and Healthy City development / 上海预防医学

The paper highlights the three key words:city, health and development.On the one hand, it is necessary to understand the city with systematic thinking, to focus on the health gap and health equity of different populations in the same city, and the continuous spectrum of health indicators or disease distribution in the same population.On the other hand, it is suggested to establish a "participatory governance" model in Healthy City development-government for health, to further promote the development of healthy cities.Finally, it briefly introduces the report of "Healthy City 2.0-Towards a Planet City" presented by Professor Hancock at the 23rd International Conference on Health Promotion of IUHPE, 2019 in New Zealand.

Comparison of the early control process of H7N9 avian influenza in Shanghai and COVID-19 in Wuhan / 上海预防医学

Objective To analyze and estimate the possibility of early control in Shanghai if COVID-19 had begun in Shanghai. Methods Comparison was made in the processes of early control between H7N9 avian influenza in Shanghai in 2013 and COVID-19 in Wuhan in 2019.The early incidence data of Korean COVID-19 was simulated and analyzed to predict whether the medical resources needed in Shanghai were available. Results If it had occurred in Shanghai, it would have taken 22 days from the first case to the government′s emergency response.It was estimated that there would have been 602-763 patients with cumulative onset and onset after incubation period.At least 500 beds of infectious diseases could have been allocated in Shanghai in case of emergency.Through adding beds and resources reallocation in the whole city, patients could have been fully admitted and treated. Conclusion If COVID-19 epidemic had occurred in Shanghai, it′s early control would have been possible though there might have difficulties.

Comparing the process of early control of government between H7N9 avian influenza in Shanghai in 2013 and COVID-19 in Wuhan in 2019 / 上海预防医学

[Objective] To analyze and judge the possibility of early control in Shanghai if COVID-19 begins in Shanghai. [Methods] Compare the process of early control of H7N9 avian influenza in Shanghai in 2013 and Wuhan COVID-19 in 2019. The early incidence data of Korean COVID-19 was simulated and analyzed to predict whether the medical resources needed in Shanghai were available. [Results] (1) It would take 22 days from the first case to the government's emergency response in terms of Shanghai. (2) It is estimated that there would be 602-763 patients with cumulative onset and onset after incubation period. (3) At least 500 beds of infectious diseases can be allocated in Shanghai in case of emergency. Through adding beds and resources reallocation in the whole city, patients can be fully admitted and treated. [Conclusion] If COVID-19 epidemic occurs in Shanghai, early control is possible.

Clinical efficacy comparison of moxibustion with different doses for knee osteoarthritis / 针灸推拿医学（英文版）

Objective: To compare the efficacy of moxibustion with different doses for knee osteoarthritis (KOA), and explore the correlation between moxibustion dose and clinical efficacy. Methods: Sixty-eight patients with KOA who met the inclusion criteria were randomly divided into a 20-minute moxibustion group and a 40-minute moxibustion group by the random number table method, with 34 cases in each group. Dubi (ST 35), Neixiyan (EX-LE 4) and Heding (EX-LE 2) were used for moxibustion in the two groups. Each treatment lasted 20 min or 40 min for each point in the 20-minute moxibustion group and 40-minute moxibustion group, separately; the treatment was given 3 times a week and lasted for 4 weeks. The visual analog scale (VAS), Western Ontario and McMaster University osteoarthritis index (WOMAC) and traditional Chinese medicine (TCM) symptom scores were evaluated before and after treatment to compare the efficacy between different moxibustion doses for KOA. Results: After treatment, the total effective rate was 87.5％ in the 40-minute moxibustion group, versus 70.0％ in the 20-minute moxibustion group, and the difference in the total effective rate between the two groups was statistically significant (P<0.05). After treatment, the VAS scores, the total WOMAC scores and the component scores of pain, stiffness and dysfunction, and the TCM symptom scores in both groups all changed significantly when compared with those before treatment (all P<0.05). After treatment, the between-group differences in the VAS score, the total WOMAC score and the component scores of pain and dysfunction, and the TCM symptom score were statistically significant (all P<0.05), while the difference in the stiffness score in WOMAC showed no statistical significance (P>0.05). Conclusion: Either 20-minute moxibustion or 40-minute moxibustion can relieve pain, improve stiffness, dysfunction, and TCM symptoms for KOA; and 40-minute moxibustion is better in relieving pain, improving dysfunction and TCM symptoms.

Clinical study on mild moxibustion for knee osteoarthritis / 针灸推拿医学（英文版）

Objective:To observe the clinical effect of mild moxibustion for knee osteoarthritis (KOA) and to explore the role of mild moxibustion in relieving pain,reducing stiffness and improving joint dysfunction in patients with KOA.Methods:Eighty patients with KOA were randomly allocated into either a moxibustion group or a medication group by the random number table,with 40 cases in each group.The moxibustion group used mild moxibustion at Neixiyan (EX-LE 5),Dubi (ST 35),Xuehai (SP 10) and Liangqiu (ST 34),30 min each time,3 times a week;the medication group was given celecoxib capsule (celebrex),0.2 g each time,once a day.Both groups were treated for 4 weeks.The visual analog scale (VAS) and Western Ontario and McMaster Universities osteoarthritis index (WOMAC)scores were evaluated before and after treatment.The efficacy of the two groups was compared after treatment.Results:After treatment,the overall efficacy of the moxibustion group was significantly different from that of the medication group (P＜0.05).The VAS and WOMAC scores of the two groups were lower than those before treatment (both P＜0.01).The changes in the VAS and WOMAC scores after treatment in the moxibustion group were significantly different from those in the medication group (both P＜0.05).After treatment,in single item of WOMAC,the changes in pain and joint dysfunction in the moxibustion group were more statistically significant than those in the medication group (both P＜0.05).Conclusion:Mild moxibustion and oral celebrex can reduce the VAS and WOMAC scores of patients with KOA.Mild moxibustion is superior to oral celebrex in relieving pain and improving joint function.

Alternaria yunnanensis sp. nov., a New Alternaria Species Causing Foliage Spot of Rubber Tree in China

A new species of Alternaria causing leaf spots on the rubber tree (Hevea brasiliensis) in Yunnan, China, was isolated, examined, and illustrated. Morphologically, it belongs to the section Porri of Alternaria, which produces relatively large conidia and a simple or branched, filamentous long beak. It is, however, characterized by conidiophores gradually enlarging near the apex into a clavate conidiogenous cell and long ellipsoid to obclavate, smooth-walled conidia with a long filamentous beak. Molecular phylogenetic analyses based on ITS rDNA, GAPDH, and TEF1-alpha sequences demonstrate that the phytopathogen falls in the clade of the section Porri, being most closely related to A. sidae, A. sennae, A. deseriticola, A. cyamopsidis, A. rostellata, A. nitrimali, A. crassa, and A. thunbergiae.

Calcitriol enhances pyrazinamide treatment of murine tuberculosis / 中华医学杂志(英文版)

BACKGROUND@#Tuberculosis is a leading cause of morbidity and mortality in humans worldwide. There is an urgent need for new and effective drugs to treat tuberculosis and shorten the duration of tuberculosis therapy. 1, 25-dihydroxy vitamin D3 (1,25 (OH)2D3) has been reported to have a synergistic effect with pyrazinamide (PZA) in killing tubercle bacilli in vitro. The addition of 1,25 (OH)2D3 to standard tuberculosis treatment should benefit patients if the adjunctive drug has a synergistic effect in vivo. Thus, in this study, calcitriol (bioactive 1,25 (OH)2D3) was administered to mice undergoing treatment for Mycobacterium tuberculosis (M.tb) infection with PZA, a first-line anti-tuberculosis drug, to determine whether vitamin D3 enhances the therapeutic effect.@*METHODS@#C57BL/6 female mice were infected with the M.tb H37Rv strain through aerosol exposure. Calcitriol and PZA, either alone or in combination, were orally administered to the M.tb infected mice. The effect of calcitriol on PZA activity was determined by evaluating the bacterial burden and analyzing the histopathological lesions in the lungs and spleen. To investigate the expression of inflammatory cytokines and anti-microbial peptide genes, we determined the transcriptional levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), mouse β-defensin-2 (mBD2), and cathelicidin LL-37 through real-time quantitative polymerase chain reaction. The protein levels of IFN-γ were detected by enzyme-linked immunosorbent assay. Differences between groups were analyzed with independent samples t-test or one-way analysis of variance.@*RESULTS@#Calcitriol alone had little effect on tuberculosis infection, whereas PZA, compared with saline control treatment, decreased the bacterial burden (spleens: PZA vs. saline, 4.82 ± 0.22 vs. 5.22 ± 0.40 Log10 colony-forming units [CFU]/gram, t = 2.13, P < 0.05; lungs: PZA vs. saline, 5.55 ± 0.15 vs. 6.83 ± 0.46 Log10 CFU/gram, t = 6.56, P < 0.01) and pathological lesions in the lungs. Simultaneous administration of calcitriol with PZA, compared with PZA alone, decreased the bacterial load (spleen: calcitriol + PZA vs. PZA, 4.37 ± 0.13 vs. 4.82 ± 0.22 Log10 CFU/gram, t = 4.36, P < 0.01; lung: calcitriol + PZA vs. PZA, 5.03 ± 0.32 vs. 5.55 ± 0.15 Log10 CFU/gram, t = 3.58, P < 0.01) and attenuated the lung lesions (gross pathological score: calcitriol + PZA vs. PZA, 3.25 ± 0.50 vs. 2.50 ± 0.58, t = 1.96, P < 0.05; affected area of total lung area: calcitriol + PZA vs. PZA, 30.75% ± 6.50% vs. 21.55% ± 2.99%, t = 2.66, P < 0.05). Further studies demonstrated calcitriol significantly increased the expression of anti-inflammatory cytokine IL-4 but suppressed production of the pro-inflammatory cytokine IFN-γ (IL-4: calcitriol vs. saline, 5.69 ± 0.50 vs. 2.80 ± 0.56 fold of control, t = 6.74, P < 0.01; IFN-γ: calcitriol vs. saline, 1.36 ± 0.11 vs. 4.13 ± 0.83 fold of control, t = 5.77, P < 0.01). In addition, calcitriol alone or in combination with PZA significantly enhanced the transcriptional level of anti-microbial peptides (cathelicidin LL-37: calcitriol vs. saline, 10.59 ± 1.03 vs. 2.80 ± 0.90 fold of control, t = 9.85, P < 0.01; mBD2: calcitriol vs. saline, 7.92 ± 0.62 vs. 1.79 ± 0.45 fold of control, t = 13.82, P < 0.01), whereas PZA exerted a negative effect on anti-microbial peptide gene expression.@*CONCLUSIONS@#Calcitriol as adjunctive treatment can result in beneficial treatment outcomes in M.tb infection by suppressing the inflammatory response and up-regulating the expression of anti-microbial peptides. These results indicate the feasibility of using calcitriol adjunctively with standard chemotherapy for the treatment of M.tb infection.

Calcitriol enhances pyrazinamide treatment of murine tuberculosis / 中华医学杂志(英文版)

Background@#Tuberculosis is a leading cause of morbidity and mortality in humans worldwide. There is an urgent need for new and effective drugs to treat tuberculosis and shorten the duration of tuberculosis therapy. 1, 25-dihydroxy vitamin D3 (1,25 (OH)2D3) has been reported to have a synergistic effect with pyrazinamide (PZA) in killing tubercle bacilli in vitro. The addition of 1,25 (OH)2D3 to standard tuberculosis treatment should benefit patients if the adjunctive drug has a synergistic effect in vivo. Thus, in this study, calcitriol (bioactive 1,25 (OH)2D3) was administered to mice undergoing treatment for Mycobacterium tuberculosis (M.tb) infection with PZA, a first-line anti-tuberculosis drug, to determine whether vitamin D3 enhances the therapeutic effect.@*Methods@#C57BL/6 female mice were infected with the M.tb H37Rv strain through aerosol exposure. Calcitriol and PZA, either alone or in combination, were orally administered to the M.tb infected mice. The effect of calcitriol on PZA activity was determined by evaluating the bacterial burden and analyzing the histopathological lesions in the lungs and spleen. To investigate the expression of inflammatory cytokines and anti-microbial peptide genes, we determined the transcriptional levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), mouse β-defensin-2 (mBD2), and cathelicidin LL-37 through real-time quantitative polymerase chain reaction. The protein levels of IFN-γ were detected by enzyme-linked immunosorbent assay. Differences between groups were analyzed with independent samples t-test or one-way analysis of variance.@*Results@#Calcitriol alone had little effect on tuberculosis infection, whereas PZA, compared with saline control treatment, decreased the bacterial burden (spleens: PZA vs. saline, 4.82 ± 0.22 vs. 5.22 ± 0.40 Log10 colony-forming units [CFU]/gram, t = 2.13, P < 0.05; lungs: PZA vs. saline, 5.55 ± 0.15 vs. 6.83 ± 0.46 Log10 CFU/gram, t = 6.56, P < 0.01) and pathological lesions in the lungs. Simultaneous administration of calcitriol with PZA, compared with PZA alone, decreased the bacterial load (spleen: calcitriol + PZA vs. PZA, 4.37 ± 0.13 vs. 4.82 ± 0.22 Log10 CFU/gram, t = 4.36, P < 0.01; lung: calcitriol + PZA vs. PZA, 5.03 ± 0.32 vs. 5.55 ± 0.15 Log10 CFU/gram, t = 3.58, P < 0.01) and attenuated the lung lesions (gross pathological score: calcitriol + PZA vs. PZA, 3.25 ± 0.50 vs. 2.50 ± 0.58, t = 1.96, P < 0.05; affected area of total lung area: calcitriol + PZA vs. PZA, 30.75% ± 6.50% vs. 21.55% ± 2.99%, t = 2.66, P < 0.05). Further studies demonstrated calcitriol significantly increased the expression of anti-inflammatory cytokine IL-4 but suppressed production of the pro-inflammatory cytokine IFN-γ (IL-4: calcitriol vs. saline, 5.69 ± 0.50 vs. 2.80 ± 0.56 fold of control, t= 6.74, P < 0.01; IFN-γ: calcitriol vs. saline, 1.36 ± 0.11 vs. 4.13 ± 0.83 fold of control, t= 5.77, P < 0.01). In addition, calcitriol alone or in combination with PZA significantly enhanced the transcriptional level of anti-microbial peptides (cathelicidin LL-37: calcitriol vs. saline, 10.59 ± 1.03 vs. 2.80 ± 0.90 fold of control, t = 9.85, P < 0.01; mBD2: calcitriol vs. saline, 7.92 ± 0.62 vs. 1.79 ± 0.45 fold of control, t = 13.82, P < 0.01), whereas PZA exerted a negative effect on anti-microbial peptide gene expression.@*Conclusions@#Calcitriol as adjunctive treatment can result in beneficial treatment outcomes in M.tb infection by suppressing the inflammatory response and up-regulating the expression of anti-microbial peptides. These results indicate the feasibility of using calcitriol adjunctively with standard chemotherapy for the treatment of M.tb infection.