1.Mitochondria: The Target of Ionizing Radiation Damage
Lian-Chen TIAN ; Ya-Yi YUAN ; Xu-Hong DANG
Progress in Biochemistry and Biophysics 2025;52(4):836-844
In recent years, due to the development of radiotherapy technology and nuclear energy, people have paid more and more attention to the various effects of ionizing radiation on organisms. Ionizing radiation can induce protein, DNA and other biological macromolecules to damage, resulting in apoptosis, senescence, cancer and a series of changes. For a long time, it has been believed that the main target of ionizing radiation damage is DNA in the nucleus. However, it has been reported in recent years that ionizing radiation has both direct and indirect effects, and the theory of ROS damage in the indirect effects believes that ionizing radiation has target uncertainty, so it is not comprehensive enough to evaluate only the DNA damage in the nucleus. It has been reported that ionizing radiation can cause damage to organelles as well as damage to cells. Mitochondria are important damaged organelles because mitochondria occupy as much as 30% of the entire cell volume in the cytoplasm, which contains DNA and related enzymes that are closely related to cellular ATP synthesis, aerobic respiration and other life activities. What is more noteworthy is that mitochondria are the only organelles in which DNA exists in the human body, which makes researchers pay attention to various damage to mitochondrial DNA caused by ionizing radiation (such as double-strand breaks, base mismatching, and fragment loss). Although these damages also occur in the nucleus, mitochondrial DNA is more severely damaged than nuclear DNA due to its lack of histone protection, so mitochondria are important targets of ionizing radiation damage in addition to the nucleus. Mitochondrial DNA is not protected by histones and has little repair ability. When exposed to ionizing radiation, common deletions occur at an increased frequency and are passed on to offspring. For large-scale mitochondrial DNA damage, mitochondria indirectly compensate for the amount of damaged DNA by increasing the number of DNA copies and maintaining the normal function of mitochondrial DNA. Mitochondria are in a state of oxidative stress after exposure to ionizing radiation, and this oxidative stress will promote the change in mitochondrial function. When mitochondria are damaged, the activity of proteins related to aerobic respiration decreases, and oxidative respiration is inhibited to a certain extent. At the same time, a large amount of active superoxide anions are continuously produced to stimulate mitochondrial oxidative stress, and the signal of such damage is transmitted to the surrounding mitochondria, resulting in a cascade of damage reaction, which further activates the signalling pathway between mitochondria and nucleus. The cell nucleus is also in a state of oxidative stress, and finally, the level of free radicals is high, causing secondary damage to the genetic material DNA of mitochondria and nucleus. In this paper, the damage effects of ionizing radiation on mitochondria are reviewed, to provide a new idea for radiation protection.
2.Clinical features and early warning indicators of patients with acute-on-chronic liver failure and bacterial infection
Zhanhu BI ; Linxu WANG ; Haifeng HU ; Hong DU ; Yidi DING ; Xiaofei YANG ; Jiayi ZHAN ; Fei HU ; Denghui YU ; Hongkai XU ; Jianqi LIAN
Journal of Clinical Hepatology 2024;40(4):760-766
ObjectiveTo investigate the clinical features of patients with acute-on-chronic liver failure (ACLF) and bacterial infection and early warning indicators associated with multidrug-resistant infections. MethodsA retrospective analysis was performed for 130 patients with ACLF and bacterial infection who attended The Second Affiliated Hospital of Air Force Medical University from January 1, 2010 to December 31, 2021, and according to the drug susceptibility results, the patients were divided into multidrug-resistant (MDR) bacterial infection group with 80 patients and non-MDR bacterial infection group with 50 patients. General information and laboratory examination results were compared between the two groups to screen for the early warning indicators associated with MDR bacterial infection. The Student’s t-test was used for comparison of normally distributed continuous data with homogeneity of variance between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data or continuous data with heterogeneity of variance between two groups; the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups. The binary logistic regression analysis and the receiver operating characteristic (ROC) curve were used to assess the predictive value of early warning indicators. ResultsAmong the 130 patients with ACLF and bacterial infection, sputum (27.7%) was the most common specimen for detection, followed by blood (24.6%), urine (18.5%), and ascites (17.7%). Bacterial infections were dominated by Gram-negative bacteria (58.5%). Of all bacteria, Escherichia coli (18.5%), Klebsiella pneumoniae (14.6%), and Enterococcus faecium (13.8%) were the most common pathogens. Gram-positive bacteria had a high resistance rate to the antibacterial drugs such as erythromycin (72.2%), penicillin (57.4%), ampicillin (55.6%), and ciprofloxacin (53.7%), while Gram-negative bacteria had a high resistance rate to the antibacterial drugs such as ampicillin (73.3%), cefazolin (50.0%), and cefepime (47.4%). The patients with ACLF and bacterial infection had a relatively high rate of MDR bacterial infection (61.5%). Comparison of clinical data between the two groups showed that compared with the patients with non-MDR bacterial infection, the patients with MDR bacterial infection had significantly higher levels of alanine aminotransferase (Z=2.089, P=0.037), aspartate aminotransferase (Z=2.063, P=0.039), white blood cell count (Z=2.207, P=0.027), and monocyte count (Z=4.413, P<0.001). The binary logistic regression analysis showed that monocyte count was an independent risk factor for MDR bacterial infection (odds ratio=7.120, 95% confidence interval [CI]: 2.478 — 20.456,P<0.001) and had an area under the ROC curve of 0.686 (95%CI: 0.597 — 0.776) in predicting ACLF with MDR bacterial infection(P<0.001), with the optimal cut-off value of 0.50×109/L, a sensitivity of 0.725, and a specificity of 0.400. ConclusionACLF combined with bacterial infections is mainly caused by Gram-negative bacteria, with the common pathogens of Escherichia coli and Klebsiella pneumoniae and a relatively high MDR rate in clinical practice. An increase in monocyte count can be used as an early warning indicator to distinguish MDR bacterial infection from non-MDR bacterial infection.
3.Vulnerability of medicinal plant Lamiophlomis rotata under future climate changes
Hong-chao WANG ; Zheng-wei XIE ; Qi-ao MA ; Tie-lin WANG ; Guang YANG ; Xiao-ting XU ; Kai SUN ; Xiu-lian CHI
Acta Pharmaceutica Sinica 2024;59(10):2871-2879
italic>Lamiophlomis rotata is an important medicinal plant species endemic to the Tibetan Plateau, which is prone to strong climate change impacts on its habitable range due to the high sensitivity of the Tibetan Plateau to climate change. Accurate quantification of species vulnerability to climate change is essential for assessing species extinction risk and developing effective conservation strategies. Therefore, we carried out the
4.Establishment and application for evaluation system of pathogen detection rate indicators before antimicrobial treatment
Lei-Lei GUO ; Hong-Ying QIN ; Sai-Nan XU ; Zhen-Zhen WU ; Yi ZHANG ; Shang-Shu ZHANG ; Hong-Kai LIAN
Chinese Journal of Infection Control 2024;23(6):712-718
Objective To establish an evaluation system of pathogen detection rate of hospitalized patients before antimicrobial treatment based on process and outcome indicators,and study its application effect.Methods Hospi-talized patients with therapeutic antimicrobial treatment in a tertiary first-class hospital from July 2022 to June 2023 were selected as the study objects.Difference in process and outcome indicators were compared between before(Ju-ly-December 2022,control group)and after(January-June 2023,intervention group)the implementation of inter-vention in the evaluation system for pathogen detection rate of hospitalized patients before antimicrobial treatment.Results 41 577 and 27 052 hospitalized patients received therapeutic antimicrobial agents were included in the inter-vention group and control group,respectively.Pathogen detection rate and the accurate pathogen detection rate in the intervention group were both higher than those in the control group(74.2%vs 62.8%and 90.3%vs 82.5%,respectively),both with statistically significant differences(both P<0.001).The goal achievement rate and im-provement rate for pathogen detection rate were 237.5%and 18.2%respectively,the goal achievement rate and im-provement rate for accurate pathogen detection rate were 104.0%and 9.5%respectively.For the process indica-tors,the conformity rate of detection and diagnosis,accurate collection rate,timely transfer rate,acceptance rate of pathogen specimens in the intervention group were all higher than those in the control group,differences were all statistically significant(all P<0.001).For the outcome indicators,detection rates of targeted indicators and blood culture specimens,pathogen detection rate before treatment of restricted and special grade antimicrobial agent,as well as detection rate of sterile body fluid specimens in the intervention group were all higher than those in the con-trol group,with statistical significance(all P<0.05).In addition,the positive rate of blood culture specimens in-creased from 18.5%before intervention to 21.7%after intervention,with statistically significant difference(P<0.05).Conclusion The establishment of indicator evaluation system can improve the detection rate and accurate detection rate of pathogens before antimicrobial treatment,as well as the management quality and connotation of indicators.
5.Based on Wnt/β-Catenin Signal Pathway to Explore the Mechanism of Tongluotangtai Recipe on GK Rats with Diabetes Peripheral Neuropathy
Jiushu YUAN ; Xueru WANG ; Susu HUANG ; Jie XU ; Huixuan ZHANG ; Hong GAO ; Lian DU ; Chunguang XIE
World Science and Technology-Modernization of Traditional Chinese Medicine 2023;25(9):2950-2958
Objective Exploring the effect of Tong luo tang tai(TLTT)on diabetic peripheral neuropathy(DPN)in GK rats with Wnt/β-The influence of the catenin signaling pathway.Methods Fifty GK rats were randomly divided into model group,TLTT high,medium,and low dose groups,and Western medicine group,with 10 rats in each group.Another 10 wistar rats were selected as the normal group.Except for the normal group,all other groups were fed with high fat to prepare DPN rat models.After 15 weeks,the DPN model was successfully prepared,and the rats in each group were treated by gavage.The high,medium,and low dose groups of TLTT were given traditional Chinese medicine TLTT 28 g·kg-1,14 g·kg-1,and 7 g·kg-1,respectively.The western medicine group was given metformin 100 mg·kg-1 and mecobalamin 0.2 mg·kg-1 by gavage.Rats in each group were administered once a day for 8 consecutive weeks.The general state,fasting blood sugar(FBS),thermal contraction latency(TWL),motor nerve conduction velocity(MNCV),and pathological changes in the sciatic nerve tissue were observed under transmission electron microscopy(Real time PCR)Western blot detection of wingless MMTV integration site family member 3A(Wnt3a)β Catenin(β-Catenin,Glycogen Synthesis Kinase-3β Glycogen synthesis kinase-3β,GSK-3β)MRNA and protein expression levels of antagonists(WNT inhibitor factor-1,Wif-1)on the Wnt signaling pathway.Results Compared with the normal group,the model group showed poorer general condition and significant pathological ultrastructural changes in the sciatic nerve.Its FBS level increased(P<0.01),TWL level decreased(P<0.01),and MNCV significantly slowed down(P<0.01).The model group had Wnt3a β-Catenin,GSK-3β MRNA and protein expression levels decreased(P<0.05),while Wif-1 mRNA and protein expression levels increased(P<0.01).After drug intervention,compared with the model group,the general condition and pathological ultrastructure of the sciatic nerve were improved in the TLTT high,medium,low,dose,and Western medicine groups,with a decrease in FBS levels(P<0.01)and an increase in TWL levels(P<0.05).The MNCV of each TLTT dose group and Western medicine group was significantly improved(P<0.01).The Wnt3amRNA of the TLTT high-dose group and Western medicine group was significantly increased(P<0.05),while the Wif-1mRNA of the TLTT high-dose group and Western medicine group was significantly reduced(P<0.05),There was a significant increase in Wnt3 protein in the high-dose and Western medicine groups of TLTT(P<0.01),as well as in the high-dose,medium,and low-dose TLTT and western medicine groups β-Catenin protein significantly increased(P<0.01,P<0.05),with high,medium,and low doses of TLTT and Western medicine group GSK-3β The protein significantly increased(P<0.01,P<0.05),while the Wif-1 protein significantly decreased(P<0.01,P<0.05)in the high and medium dose TTLTT and western medicine groups.Conclusion Tongluo Tangtai can alleviate sciatic nerve injury in DPN to a certain extent,and its mechanism may be related to the activation of Wnt/β,the catenin signaling pathway is involved.
6.Causative Microorganisms Isolated from Patients with Intra-Abdominal Infections and Their Drug Resistance Profiles: An 11-Year (2011-2021) Single-Center Retrospective Study.
Rui DING ; Rui Rui MA ; Ya Li LIU ; Ying ZHAO ; Li Na GUO ; Hong Tao DOU ; Hong Li SUN ; Wen Jing LIU ; Li ZHANG ; Yao WANG ; Ding Ding LI ; Qiao Lian YI ; Ying Chun XU
Biomedical and Environmental Sciences 2023;36(8):732-742
OBJECTIVE:
To investigate the distribution and antimicrobial susceptibility of causative microorganisms recovered from patients with intra-abdominal infections (IAIs).
METHODS:
A total of 2,926 bacterial and fungal strains were identified in samples collected from 1,679 patients with IAIs at the Peking Union Medical College Hospital between 2011 and 2021. Pathogenic bacteria and fungi were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Antimicrobial susceptibility testing (AST) was performed using the VITEK 2 compact system and the Kirby-Bauer method. AST results were interpreted based on the M100-Ed31 clinical breakpoints of the Clinical and Laboratory Standards Institute.
RESULTS:
Of the 2,926 strains identified, 49.2%, 40.8%, and 9.5% were gram-negative bacteria, gram-positive bacteria, and fungi, respectively. Escherichia coli was the most prevalent pathogen in intensive care unit (ICU) and non-ICU patients; however, a significant decrease was observed in the isolation of E. coli between 2011 and 2021. Specifically, significant decreases were observed between 2011 and 2021 in the levels of extended-spectrum β-lactamase (ESBL)-producing E. coli (from 76.9% to 14.3%) and Klebsiella pneumoniae (from 45.8% to 4.8%). Polymicrobial infections, particularly those involving co-infection with gram-positive and gram-negative bacteria, were commonly observed in IAI patients. Moreover, Candida albicans was more commonly isolated from hospital-associated IAI samples, while Staphylococcus epidermidis had a higher ratio in community-associated IAIs. Additionally, AST results revealed that most antimicrobial agents performed better in non-ESBL-producers than in ESBL-producers, while the overall resistance rates (56.9%-76.8%) of Acinetobacter baumanmii were higher against all antimicrobial agents than those of other common gram-negative bacteria. Indeed, Enterococcus faecium, Enterococcus faecalis, S. epidermidis, and S. aureus were consistently found to be susceptible to vancomycin, teicoplanin, and linezolid. Similarly, C. albicans exhibited high susceptibility to all the tested antifungal drugs.
CONCLUSION
The distribution and antimicrobial susceptibility of the causative microorganisms from patients with IAIs were altered between 2011 and 2021. This finding is valuable for the implementation of evidence-based antimicrobial therapy and provides guidance for the control of hospital infections.
Humans
;
Anti-Bacterial Agents
;
Escherichia coli
;
Gram-Negative Bacteria
;
Gram-Positive Bacteria
;
Retrospective Studies
;
Staphylococcus aureus
;
Intraabdominal Infections/epidemiology*
;
Candida albicans
;
Coinfection
7.Factors influencing the sperm retrieval rate of microdissection testicular sperm extraction in patients with nonmosaic Klinefelter syndrome.
De-Feng LIU ; Han WU ; Zhe ZHANG ; Kai HONG ; Hao-Cheng LIN ; Jia-Ming MAO ; Hui-Yu XU ; Lian-Ming ZHAO ; Hui JIANG
Asian Journal of Andrology 2023;25(6):704-707
To investigate the factors affecting the sperm retrieval rate of microdissection testicular sperm extraction (micro-TESE) in patients with nonmosaic Klinefelter syndrome (KS), 64 patients with nonmosaic KS who underwent micro-TESE in the Center for Reproductive Medicine of Peking University Third Hospital (Beijing, China) between January 2016 and December 2017 were included in the study. Data on medical history, physical examination and laboratory examination results, and micro-TESE outcomes were collected. Patients were divided into two groups according to micro-TESE outcomes. The following factors were compared between the two groups by the Mann‒Whitney U test or Student's t-test based on the distribution (nonnormal or normal) of the factors: age, testicular size, follicle-stimulating hormone level, luteinizing hormone level, testosterone level, and anti-Müllerian hormone level. The overall success rate of sperm retrieval was 50.0%. Correlation analysis showed that testicular volume was positively correlated with testosterone level. Using a logistic regression model, age and anti-Müllerian hormone levels were found to be better predictors for the sperm retrieval rate than the other parameters.
Humans
;
Male
;
Sperm Retrieval
;
Klinefelter Syndrome
;
Microdissection
;
Anti-Mullerian Hormone
;
Semen
;
Testis
;
Spermatozoa
;
Testosterone
;
Azoospermia
;
Retrospective Studies
8.Analysis of refractive parameters and theirs correlation with spherical equivalent in preschool children aged 3 to 6 years
Tong LI ; Rui YU ; Feng-Yi ZHANG ; Ya-Tong WANG ; Hao XU ; Hong-Lian GAO ; Lei ZHANG
International Eye Science 2023;23(7):1189-1195
AIM: To investigate the distribution of refractive parameters and theirs correlation with spherical equivalent(SE)in preschool children aged 3 to 6 years, and evaluate the accuracy of each screening index in diagnosing refractive errors.METHODS: Cross-sectional study. A total of 791 preschool children, ranging from 3 to 6 years old, who consented to undergo mydriatic refraction were selected. Axial length(AL), corneal refractive power(K), and SE were measured after microcoria optometry and mydriatic optometry. Additionally, the corneal radius of curvature(CR)and the axial length/corneal radius of curvature(AL/CR)ratio were calculated.RESULTS: A total of 791 students participated in the study, out of which 400(50.6%)were male and 391(49.4%)were female. The mean values for AL, CR, AL/CR, and SE were 22.62±0.94mm, 7.81±0.29mm, 2.90±0.09, and +1.95±1.31D, respectively. AL, CR, and AL/CR increased with age. AL and CR were significantly higher in males than in females(all P<0.001), while there was no statistically significant difference between AL/CR and SE in males and females(P=0.82, 0.19). The correlation coefficients of SE and AL/CR, AL and CR were -0.86, -0.50 and 0.16, respectively. The results of multiple linear regression analysis indicate that for each unit increase in AL/CR, there was a corresponding shift of 10.91 towards myopia in SE. The sensitivity of AL/CR in screening for myopia was 94.44%, with a specificity of 90.46% and a Youden index of 0.84. For screening myopia under microcoria optometry, the sensitivity was 100%, with a specificity of 66.09% and a Youden index of 0.66. The area under the curve was 0.967 and 0.809 when the ROC curves were plotted using AL/CR and AL as indicators for screening myopia, respectively.CONCLUSION: For large group screening activities where mydriatic optometry is not feasible, AL/CR is better for evaluating refractive status and identifying children with myopia and hyperopia reserve that are lower than normal for their age, compared to AL and microcoria optometry.
9.Effects of Zishen Yutai Pills on in vitro Fertilization-Embryo Transfer Outcomes in Patients with Diminished Ovarian Reserve: A Prospective, Open-Labeled, Randomized and Controlled Study.
Xiu-Fang LI ; Zhong-Qing WANG ; Hai-Yan XU ; Hong LIU ; Yan SHENG ; Jin XU ; Yuan-Mei LI ; Fang LIAN
Chinese journal of integrative medicine 2023;29(4):291-298
OBJECTIVE:
To explore the effects of Zishen Yutai Pills (ZYPs) on the quality of oocytes and embryos, as well as pregnancy outcomes in patients with diminished ovarian reserve (DOR) receiving in vitro fertilization-embryo transfer (IVF-ET). The possible mechanisms, involving the regulation of bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9), were also investigated.
METHODS:
A total of 120 patients with DOR who underwent their IVF-ET cycle were randomly allocated to 2 groups in a 1:1 ratio. The patients in the treatment group (60 cases) received ZYPs from the mid-luteal phase of the former menstrual cycle by using gonadotropin-releasing hormone (GnRH) antagonist protocol. The patients in the control group (60 cases) received the same protocol but without ZYPs. The primary outcomes were the number of oocytes retrieved and high-quality embryos. Secondary outcomes included other oocyte or embryo indices as well as pregnancy outcomes. Adverse events were assessed by comparison of the incidence of ectopic pregnancy, pregnancy complications, pregnancy loss, and preterm birth. Contents of BMP15 and GDF9 in the follicle fluids (FF) were also quantified with enzyme-linked immunosorbent assay.
RESULTS:
Compared with the control group, the numbers of oocytes retrieved and high-quality embryos were significantly increased in the ZYPs group (both P<0.05). After treatment with ZYPs, a significant regulation of serum sex hormones was observed, including progesterone and estradiol. Both hormones were up-regulated compared with the control group (P=0.014 and 0.008), respectively. No significant differences were observed with regard to pregnancy outcomes including implantation rates, biochemical pregnancy rates, clinical pregnancy rates, live birth rates, and pregnancy loss rates (all P>0.05). The administration of ZYPs did not increase the incidence of adverse events. The expressions of BMP15 and GDF9 in the ZYPs group were significantly up-regulated compared with the control group (both P<0.05).
CONCLUSIONS
ZYPs exhibited beneficial effects in DOR patients undergoing IVF-ET, resulting in increments of oocytes and embryos, and up-regulation of BMP15 and GDF9 expressions in the FF. However, the effects of ZYPs on pregnancy outcomes should be assessed in clinical trials with larger sample sizes (Trial reqistration No. ChiCTR2100048441).
Infant, Newborn
;
Pregnancy
;
Female
;
Humans
;
Fertilization in Vitro/methods*
;
Ovarian Reserve
;
Prospective Studies
;
Premature Birth
;
Embryo Transfer/methods*
;
Ovulation Induction/methods*
;
Gonadotropin-Releasing Hormone/therapeutic use*
10.Recompensation of complications in patients with hepatitis B virus-related decompensated cirrhosis treated with entecavir antiviral therapy.
Ting ZHANG ; You DENG ; Hai Yan KANG ; Hui Ling XIANG ; Yue Min NAN ; Jin Hua HU ; Qing Hua MENG ; Ji Lian FANG ; Jie XU ; Xiao Ming WANG ; Hong ZHAO ; Calvin Q PAN ; Ji Dong JIA ; Xiao Yuan XU ; Wen XIE
Chinese Journal of Hepatology 2023;31(7):692-697
Objective: To analyze the occurrence of recompensation conditions in patients with chronic hepatitis B virus-related decompensated cirrhosis after entecavir antiviral therapy. Methods: Patients with hepatitis B virus-related decompensated cirrhosis with ascites as the initial manifestation were prospectively enrolled. Patients who received entecavir treatment for 120 weeks and were followed up every 24 weeks (including clinical endpoint events, hematological and imaging indicators, and others) were calculated for recompensation rates according to the Baveno VII criteria. Measurement data were compared using the Student t-test or Mann-Whitney U test between groups. Categorical data were compared by the χ (2) test or Fisher's exact probability method between groups. Results: 283 of the 320 enrolled cases completed the 120-week follow-up, and 92.2% (261/283) achieved a virological response (HBV DNA 20 IU/ml). Child-Pugh and MELD scores were significantly improved after treatment (8.33 ± 1.90 vs. 5.77 ± 1.37, t = 12.70, P < 0.001; 13.37 ± 4.44 vs. 10.45 ± 4.58, t = 5.963, P < 0.001). During the 120-week follow-up period, 14 cases died, two received liver transplants, 19 developed hepatocellular cancer, 11 developed gastroesophageal variceal bleeding, and four developed hepatic encephalopathy. 60.4% (171/283) (no decompensation events occurred for 12 months) and 56.2% (159/283) (no decompensation events occurred for 12 months and improved liver function) of the patients had achieved clinical recompensation within 120 weeks. Patients with baseline MELD scores > 15 after active antiviral therapy achieved higher recompensation than patients with baseline MELD scores ≤15 [50/74 (67.6%) vs. 109/209 (52.2%), χ (2) = 5.275, P = 0.029]. Conclusion: Antiviral therapy can significantly improve the prognosis of patients with hepatitis B virus-related decompensated cirrhosis. The majority of patients (56.2%) had achieved recompensation. Patients with severe disease did not have a lower probability of recompensation at baseline than other patients.
Humans
;
Hepatitis B virus/genetics*
;
Hepatitis B, Chronic/drug therapy*
;
Antiviral Agents/adverse effects*
;
Esophageal and Gastric Varices/complications*
;
Liver Cirrhosis/complications*
;
Treatment Outcome
;
Gastrointestinal Hemorrhage/complications*
;
Hepatitis B/drug therapy*

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