1.Genetically predicted waist circumference and risk of atrial fibrillation
Wenting WANG ; Jiang-Shan TAN ; Jingyang WANG ; Wei XU ; Liting BAI ; Yu JIN ; Peng GAO ; Peiyao ZHANG ; Yixuan LI ; Yanmin YANG ; Jinping LIU
Chinese Medical Journal 2024;137(1):82-86
Introduction::Observational studies have revealed an association between waist circumference (WC) and atrial fibrillation (AF). However, it is difficult to infer a causal relationship from observational studies because the observed associations could be confounded by unknown risk factors. Therefore, the causal role of WC in AF is unclear. This study was designed to investigate the causal association between WC and AF using a two-sample Mendelian randomization (MR) analysis.Methods::In our two-sample MR analysis, the genetic variation used as an instrumental variable for MR was acquired from a genome-wide association study (GWAS) of WC (42 single nucleotide polymorphisms with a genetic significance of P <5 × 10 –8). The data of WC (from the Genetic Investigation of ANthropometric Traits consortium, containing 232,101 participants) and the data of AF (from the European Bioinformatics Institute database, containing 55,114 AF cases and 482,295 controls) were used to assess the causal role of WC on AF. Three different approaches (inverse variance weighted [IVW], MR–Egger, and weighted median regression) were used to ensure that our results more reliable. Results::All three MR analyses provided evidence of a positive causal association between high WC and AF. High WC was suggested to increase the risk of AF based on the IVW method (odds ratio [OR] = 1.43, 95% confidence interval [CI], 1.30–1.58, P = 2.51 × 10 -13). The results of MR–Egger and weighted median regression exhibited similar trends (MR–Egger OR = 1.40 [95% CI, 1.08–1.81], P = 1.61 × 10 -2; weighted median OR = 1.39 [95% CI, 1.21–1.61], P = 1.62 × 10 -6). MR–Egger intercepts and funnel plots showed no directional pleiotropic effects between high WC and AF. Conclusions::Our findings suggest that greater WC is associated with an increased risk of AF. Taking measures to reduce WC may help prevent the occurrence of AF.
2.Feasibility of low-dose CT brain perfusion scanning based on deep learning reconstruction algorithm: a preliminary study
Limin LEI ; Yuhan ZHOU ; Xiaoxu GUO ; Hui WANG ; Jinping MA ; Zhihao WANG ; Weimeng CAO ; Yuan GAO ; Yuming XU ; Songwei YUE
Chinese Journal of Radiological Medicine and Protection 2024;44(7):613-621
Objective:To compare image quality and diagnostic parameters of whole-brain CT perfusion scans under different scanning conditions and assess the utility of deep learning image reconstruction algorithm (DLIR) in reducing tube current during low-dose scans.Methods:Method A total of 105 patients with suspected acute ischemic stroke (AIS) were prospectively enrolled in the First Affiliated Hospital of Zhengzhou University from March, 2022 to March, 203 and their baseline information was recorded. All patients underwent head non-contrast CT and CT perfusion (CTP) examinations. CTP scanning was performed at 80 kV in two groups with the tube current of 150 mA (regular dose) and 100 mA (low dose), respectively. The CTP images of 150 mA group were reconstructed using filtered back-projection algorithm as well as adaptive statistical iterative reconstruction-V (ASIR-V) at 40% and 80% strength levels, which were denoted as groups A-C. The CTP images of 100 mA group were reconstructed using ASIR-V80%, DLIR-M, and DLIR-H, which were denoted as groups D-F. Clinical baseline characteristics and radiation doses were compared between the two groups under different scanning conditions. Furthermore, we assessed the subjective and objective image quality, conventional perfusion parameters, and abnormal perfusion parameters of AIS patients across the six groups of reconstructed CTP images.Results:Under the scanning conditions of 150 mA and 100 mA, 47 and 48 patients were diagnosed with AIS, respectively. There were no significant differences in the baseline characteristics between the two groups. However, there was a significant difference in the mean effective radiation dose (5.71 mSv vs. 3.80 mSv, t = 2 768.30, P < 0.001). The standard deviation (SD) of noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) of gray matter (GM) and white matter (WM) were significantly different among the six groups of reconstructed images ( F = 40.58-212.13, P < 0.001). In GM, the SD values in groups C, D, and F were lower than those in other groups ( P < 0.05), and the SNR values in groups C and F were higher than those in other groups ( P < 0.05). In WM, the SD and SNR values in groups C and F were significantly different from those in other groups ( P < 0.05). Additionally, CNR values in groups C and F were higher than those in other groups ( P < 0.05). There was no significant difference in subjective scores among groups B, C, and F ( P > 0.05). Regarding perfusion parameters in the brain GM, groups D and E had lower cerebral blood volume (CBV) values compared to groups A to C ( P < 0.05), and group F had lower CBV values than group B ( P < 0.05). In the brain WM, group D had consistently lower mean transit time (MTT) values compared to the other groups ( P < 0.05). Notably, there were no significant differences in AIS lesion detection rates and relevant diagnostic parameters across the six image groups. Conclusions:Low-tube current CTP scan combined with the DLIR-H algorithm can enhance image quality without affecting perfusion parameters such as CBV and MTT, while reducing radiation dose by 30%. This algorithm can be routinely applied in brain CTP examinations.
3.Fetal STR typing and paternity identification of early pregnancy aborted tissue based on next-generation sequencing technology
Jin ZHANG ; Kaihui LIU ; Jinping HAO ; Xueying YANG ; Xingkun ZHANG ; Wei PENG ; Xiaoyu XU ; Shan GAO ; Jingjing CHANG ; Bo LEI ; Mengnan ZHANG ; Qiujuan WANG ; Ying ZHANG
Chinese Journal of Forensic Medicine 2024;39(5):539-545
Fetal STR typing of aborted tissue has long been a major problem in forensic DNA.Especially for the first trimester abortion tissue,it is difficult to isolate the embryonic components by histomorphological means,resulting in the inability to accurately obtain the STR typing of the fetus.The mixed STR typing results of mother and fetus can provide a key basis for the identification of suspects in cases of rape-induced pregnancy.In this study,next generation sequencing was used to successfully detect mixed STR typing of mother and suspected fetus or single STR typing of suspected fetus in 4 rape-induced early pregnancy abortion tissues.Combined with Y-STR and flank sequence information,it provides a more comprehensive and reliable genetic basis for the identification of suspects.
4.Parasitic leiomyoma of abdominal wall complicated with disseminated peritoneal leiomyomatosis:A case report and literature review
Jinping ZHANG ; Lingling TONG ; Lu GAO ; Hongjing CHENG ; Minjia SHENG
Journal of Jilin University(Medicine Edition) 2024;50(5):1432-1437
Objective:To discuss the diagnosis and treatment process of the patients with parasitic leiomyoma(PM)of the abdominal wall complicated with disseminated peritoneal leiomyomatosis(DPL)after laparoscopic myomectomy,and to improve the clinical understanding and management of this condition.Methods:The clinical data of one patient with PM of the abdominal wall complicated with DPL after laparoscopic myomectomy were collected.The causes,clinical features,diagnosis,differential diagnosis and treatment process were analyzed,and the relevant literatures were reviewed.Results:The patient,a 49-year-old woman,was admitted due to a self-discovered abdominal mass lasting for one year.The physical examination results showed a palpable mass,approximately 6 cm×4 cm,in the lower left abdominal wall with poor mobility,with clear borders,and without tenderness.Another palpable mass,approximately 7 cm×5 cm,was found in the lower right abdomen with fair mobility,with clear borders,and without tenderness.The gynecological ultrasonography results showed a hypoechoic area of approximately 6.6 cm × 2.7 cm in the subcutaneous tissue below the left umbilicus and another hypoechoic area of approximately 7.6 cm×3.3 cm in the abdominal cavity below the umbilicus.The superficial ultrasonography of the local area showed a hypoechoic area of approximately 5.79 cm× 2.55 cm×4.74 cm within the left lower abdominal rectus muscle,with smooth edges,located 1.97 cm from the skin at its shallowest point and 4.73 cm at its deepest point,without penetration of the rectus sheath but adjacent to the peritoneum.The patient was diagnosed as uterine leiomyoma,abdominal mass,and post-myomectomy status.The elective surgeries for uterine leiomyoma enucleation,abdominal wall leiomyoma excision,and peritoneal leiomyoma excision were performed under combined intravenous-inhalation anesthesia.The operation procedure was successful,and the patient recovered well and was discharged smoothly.Conclusion:PM and DPL lack typical clinical features and require imaging examinations for diagnosis.Surgical exploration is the main treatment modality,and while PM and DPL are generally benign,there is a potential for malignant transformation,and the patients need further postoperative follow-up.
5.Tetrahydroxy stilbene glycoside ameliorates neuroin-flammation for Alzheimer's disease via cGAS-STING
Jinping HAO ; Boya LI ; Cengceng ZHENG ; Beibei MIAO ; Li ZHANG ; Yali LI ; Lin LI ; Xingjie LI ; Dan GAO ; Lan ZHANG
Chinese Journal of Pharmacology and Toxicology 2023;37(7):515-515
OBJECTIVE Alzheimer's disease(AD)is the most common neurodegenerative disease worldwide.Neuroinflammation is a potential target for the patients with AD.It is attributed to activated microglia and the release of various inflammatory mediators from infec-tion,ischemia and toxin accumulation.Accumulating evi-dence has indicated that the cGAS-STING pathway driven neuroinflammation in neurological disease.TSG is a main natural active ingredient that derived from polyg-onum multiflorum.Previous research from our group found that TSG has beneficial effects of anti-aging,anti-inflammatory action and improving memory function in APP/PS1 transgenic AD mice.Here,we investigated the effects of TSG on cognitive impairment and neuroinflam-mation in APP/PS1-AD mice and explore the underly-ing mechanism by which TSG ameliorates memory func-tion in the cGAS-STING-mediated inflammatory response.METHODS The Morris water mace test and the novel object recognition test were performed to test the effects of TSG on spatial learning and cognitive and memory abil-ity in APP/PS1 double transgenic AD mice model.In addi-tion,real-time quantitative PCR,Western blotting,ELISA analysis,and flow cytometry to examine gene and pro-tein expression of cGAS-STING related pro-inflammatory cytokines and chemokines.Statistical analyses were ana-lyzed using the SPSS 25.0 package by analysis of vari-ance(ANOVA).Neuman-Keuls or Tukey's multiple-com-parisons test were conducted as ANOVA justified post hoc comparisons between group means.RESULTS We demonstrated that AD transgenic mice exhibited cognitive deficits accompanied by the elevated serum and brain inflammation.The expressions of serum inflammatory cytokines and the activation of microglia in cerebral cor-tex and hippocampus were suppressed after TSG treat-ment,which was probably attributable to the decrease of cyclic GMP-AMP synthase(cGAS)and stimulator of interferon genes(STING)triggered immune response.Additionally,the data showed that TSG treatment reduced the expression level of inflammatory cytokines(IL-1β,TNF-α,IFN-β,IFN-α)in microglial cells BV2 primed with LPS and IFN-γ.CONCLUSION TSG implicated the health benefits in preventing cognitive disorders by inhib-iting neuroinflammation via cGAS-STING signalling path-way in AD.
6.Icariin ameliorates behavioral deficits and neuropa-thology in a mouse model of multiple sclerosis
Dan GAO ; Cengceng ZHENG ; Jinping HAO ; Cuicui YANY ; Chaoying HU
Chinese Journal of Pharmacology and Toxicology 2023;37(7):515-516
Multiple sclerosis(MS)is a systemic inflammatory illness of the central nervous system that involves demyelinating lesions in the myelin-rich white matter and pathology in the grey matter.Despite signifi-cant advancements in drug research for MS,the dis-ease's complex pathophysiology makes it difficult to treat the progressive forms of the disease.In this study,we identified a natural flavonoid compound icariin(ICA)as a potent effective agent for MS in ameliorating the deterioration of symptoms including the neurological defi-cit score and the body weight in a murine experimental autoimmune encephalomyelitis(EAE)model.These improvements were associated with decreased demyelin-ation in the corpus callosum and neuron loss in the hippo-campus and cortex confirmed by immunohistochemistry analysis.Meanwhile,it was observed that the activation of microglia in cerebral cortex and hippocampus were inhibited followed by the neuroinflammatory cytokines downregulation such as IL-1β,IL-6 and TNF-α after ICA treatment,which was probably attributable to the sup-pression of microglial NLRP3 inflammasome activation.Additionally,molecular docking also revealed the binding force of ICA to NLRP3 inflammasome protein complexes in vitro.Taken together,our findings have demonstrated that ICA,as pleiotropic agent,prevents EAE-induced MS by improving demyelination and neuron loss,which inter-feres with the neuroinflammation via microglial NLRP3 inflammasome activation.
7.Cost-effectiveness analysis of different screening modes for thalassemia in Hunan Province
Hui XI ; Qin LIU ; Donghua XIE ; Xu ZHOU ; Wanglan TANG ; Deguo TANG ; Chunyan ZENG ; Qiong WANG ; Xinghui NIE ; Jinping PENG ; Xiaoya GAO ; Hongliang WU ; Haoqing ZHANG ; Li QIU ; Zonghui FENG ; Shuyuan WANG ; Shuxiang ZHOU ; Jun HE ; Shihao ZHOU ; Faqun ZHOU ; Junqing ZHENG ; Hua WANG ; Junqun FANG ; Changbiao LIANG
Chinese Journal of Perinatal Medicine 2023;26(6):468-475
Objective:To analyze the costs and effectiveness of five common screening modes and genetic screening for thalassemia in China in order to find the optimal way and provide evidence for the implementation of thalassemia prevention and control projects in Hunan Province.Methods:From June 2020 to April 2021, 12 971 couples from 14 cities and autonomous prefectures in Hunan Province were selected as the study population. The diagnosis of thalassemia was based on the results of genetic testing. Results of routine blood test and hemoglobin electrophoresis were collected and analyzed. The efficacy of five screening modes, at the cut-off value of <80 fl or 82 fl for the mean corpuscular volume (MCV), was analyzed by positive predictive value, negative predictive value, Jorden index and cost-effectiveness ratio. Sensitivity analysis was used to assess the feasibility of genetic screening at different costs after fixing the costs of routine blood and hemoglobin electrophoresis. The five thalassemia screening models are as follows: Mode 1: The woman had a blood routine test first. If the result was positive, the spouse required a blood routine test. If both results were positive, a thalassemia gene test should be offered to the couple. Mode 2: Both husband and wife were screened by blood routine and hemoglobin electrophoresis. If one or both of them were positive, both would be tested for thalassemia gene. Mode 3: The couple received blood routine tests initially. If either was positive, both should receive hemoglobin electrophoresis testing. If either was positive, both parties will conduct thalassemia gene testing. Mode 4: The woman was screened by blood routine and hemoglobin electrophoresis. If any one of them was positive, the woman would be tested for thalassemia gene. If the gene test result was positive, the spouse should receive thalassemia gene. Mode 5: Both spouses conducted a blood routine test. If either was positive, both would conduct hemoglobin electrophoresis test. If both were positive, both spouses should receive thalassemia gene testing. Gene testing mode: The woman would be tested for thalassemia, and her spouse would have thalassemia test too if her result was positive.Results:When using MCV<80 fl as the cut-off for diagnosing thalassemia, the Youden indices of the five prenatal screening modes in Hunan Province were 0.551, 0.639, 0.898, 0.555 and 0.356, while when using MCV<82 fl as the cut-off, the Youden indices were 0.549, 0.629, 0.851, 0.548 and 0.356. When the MCV cut-off value was <80 fl, the missed diagnosis rates of the five screening modes were 44.44%, 0.00, 0.00, 18.52% and 62.96%, and the cost-effectiveness ratios were 21 709, 250 939, 76 870, 138 463 and 92 860 yuan (RMB)/couple, respectively. When the price of genetic testing was lower than 55 yuan (RMB), the cost-effectiveness ratio of genetic screening was lower than that of Mode 3.Conclusions:MCV<80 fl can be considered as the positive criteria in blood routine screening for thalassemia in Hunan Province, and the cost-effectiveness ratio of Mode 3 (the couple received blood routine tests initially. If either was positive, both should receive hemoglobin electrophoresis testing. If either was positive, both parties will conduct thalassemia gene testing) is the best. Genetic screening has certain advantages with the decreasing price.
8.Differences in lung function between sanitation workers and general population and the risk factors for airflow limitation
Jinhai HUANG ; Yun LI ; Junfeng LIN ; Yongyi PENG ; Wanyi JIANG ; Qingxiu XIE ; Lunfang TAN ; Shuyi LIU ; Zhenyu LIANG ; Jinping ZHENG ; Yi GAO
Chinese Journal of Health Management 2023;17(11):828-835
Objective:To compare the differences in lung function between sanitation workers and the general population undergoing routine physical examinations, and to analyze the risk factors for restricted airflow and severity of the condition in sanitation workers.Methods:This study is a large cross-sectional study called "Shanxin Respiratory Health Screening for Ten Thousand People". A total of 1 036 sanitation workers (sanitation group) and 6 701 individuals from the general population undergoing routine physical examinations (control group) were selected as the original study subjects from June 2021 to April 2022 (before matching). Both groups underwent pre-bronchodilator lung function tests, and the differences in lung function characteristics between the two groups were compared. The sanitation group also completed a questionnaire survey. Multivariate and ordinal multinomial logistic regression analysis were used to analyze the risk factors for airflow limitation and its severity.Results:A total of 1 027 individuals from the sanitation group and 999 individuals from the control group were included in the study. There were no significant differences in age, gender, height, weight, and body mass index (BMI) between the two groups (all P>0.05). The rate of airflow restriction was significantly higher in the sanitation group compared to the control group (22.88% vs 8.81%, P<0.001). In the sanitation group, there was no statistically significant difference in a self-assessment test for chronic obstructive pulmonary disease (CAT) scores between individuals with airflow restriction (235 cases) and those without airflow restriction (792 cases) [(1.50±2.50) vs (1.15±2.03) points, P=0.084]. There were no statistically significant differences in forced vital capacity (FVC) as a percentage of predicted value (FVC%pred) between the two groups. However, the sanitation group had significantly lower %pred for forced expiratory volume in one second (FEV 1%pred), FVC/FEV 1 ratio (FEV 1/FVC%pred), forced expiratory flow at 50% of FVC (FEF 50%%pred), forced expiratory flow at 75% of FVC (FEF 75%%pred), and maximal mid-expiratory flow (MMEF%pred) compared to the control group (all P<0.05). The rates of abnormal FEF 50%%pred, FEF 75%%pred, and MMEF%pred were significantly higher in the sanitation group compared to the control group (17.62% vs 10.31%, 17.04% vs 10.01%, 27.26% vs 18.41%, all P<0.001). Small airway parameters and the rate of airflow restriction were significantly higher in past and current smokers of the sanitation group compared to never smokers (all P<0.05). Multifactorial analysis showed that high BMI ( OR=0.929, 95% CI: 0.885-0.974) was a protective factor for airflow restriction, while high smoking index was a risk factor ( OR=1.020, 95% CI: 1.011-1.030). Ordered multinomial logistic regression analysis showed that high BMI ( OR=0.925, 95% CI: 0.882-0.971) was a protective factor for the severity of airflow restriction, while high smoking index ( OR=1.020, 95% CI: 1.011-1.029) was a risk factor for the severity of airflow restriction. Conclusions:The incidences of airflow limitation and small airway abnormalities in sanitation workers are higher than that in general physical examination population. High smoking index and low BMI are independent risk factors for airflow limitation and its severity.
9.Predictive value of serum N-terminal pro-B-type natriuretic peptide concentration for postoperative acute kidney injury in neonates undergoing cardiac surgery: based on pROCK criteria
Peiyao ZHANG ; Yuanyuan TONG ; Yixuan LI ; Liting BAI ; Yu JIN ; Peng GAO ; Wenting WANG ; Jinxiao HU ; Jinping LIU
Chinese Journal of Anesthesiology 2022;42(4):389-393
Objective:To evaluate the predictive value of the serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration for postoperative acute kidney injury (AKI) in neonates undergoing cardiac surgery.Methods:Perioperative data of 110 consecutive neonates (≤28 days) who underwent cardiac surgery in our hospital from October 2017 to May 2021, were collected retrospectively.According to pROCK criteria, the patients were divided into AKI group and non-AKI group.Demographics, predominant diagnosis, laboratory examination, perioperative management and postoperative outcomes were compared between two groups.The concentration of serum NT-proBNP was routinely measured within 12 h after operation.Multivariate logistic regression analysis was performed for the association between serum NT-proBNP and postoperative AKI.Receiver operating characteristic curve was drawn, and the predictive value of serum NT-proBNP for postoperative AKI was determined according to the area under the curve.Results:A total of 106 neonates were enrolled, and the incidence of postoperative AKI was 54.7%.There were significant difference in the baseline hemoglobin concentration, hematocrit and serum creatinine and serum NT-proBNP concentration between AKI group and non-AKI group ( P<0.05). Multivariate logistic regression analysis indicated that NT-proBNP level was an independent risk factor for AKI after cardiac surgery in neonates ( odds ratio 2.49, 95% confidence interval 1.183-5.23, P=0.016). The area under the curve of NT-proBNP predicting AKI after cardiac surgery was 0.66 (95% confidence interval 0.56-0.76, P=0.007). Conclusions:Elevated serum NT-proBNP concentration is an independent risk factor for AKI after cardiac surgery in neonates and has a certain predictive value for AKI, and close monitoring of perioperative NT-proBNP level is helpful for early identification of high-risk neonates.
10.Analysis of clinical characteristics and laboratory findings of 131 cases of neurosyphilis
Huayang TANG ; Jinping GAO ; Ze GUO ; Jin WEI ; Jiaojiao FAN ; Xianfa TANG ; Peiguang WANG ; Xiaoming KONG ; Sen YANG
Chinese Journal of Dermatology 2020;53(10):774-780
Objective:To deeply analyze differences in characteristics of neurosyphilis between male and female patients with neurosyphilis, as well as between patients with symptomatic neurosyphilis and those with asymptomatic neurosyphilis, and to provide reference for the prevention and control, clinical diagnosis and treatment of neurosyphilis.Methods:A total of 131 inpatients with neurosyphilis were collected from Department of Dermatology and Venereology, the First Affiliated Hospital of Anhui Medical University from June 2015 to December 2019, and their clinical manifestations and laboratory findings were retrospectively analyzed. These patients were grouped according to gender and neurological/psychiatric symptoms. Measurement data were compared by using two-independent-sample t test or Mann-Whitney U test, and enumeration data were compared by using chi-square test and Fisher′s exact test, to analyze differences in clinical characteristics and laboratory indicators between different groups. Results:Among the 131 patients, there were 72 with asymptomatic neurosyphilis (asymptomatic group) and 59 with symptomatic neurosyphilis (symptomatic group). The proportion of patients receiving syphilis treatment was significantly lower in the symptomatic group (10.17%) than in the asymptomatic group (98.61%, OR = 0.002, P < 0.001). The misdiagnosis rate at the first clinical visit was significantly higher in the male patients (50.00%) than in the female patients (24.49%, OR = 3.08, P = 0.004), as well as in the symptomatic patients (89.83%) than in the asymptomatic patients (0, OR = 13.00, P < 0.001). The proportion of symptomatic patients was significantly higher in male patients (57.32%) than in female patients (14.64%, OR = 4.14, P = 0.003). Compared with the female patients, the male patients showed significantly increased positive rates of toluidine red unheated serum test (TRUST) in the cerebrospinal fluid samples (52.44% vs. 26.54%, OR = 3.05, P = 0.004), increased proportions of patients with elevated levels of total protein (> 0.5 g/L) in cerebrospinal fluids (79.27% vs. 59.18%, OR = 2.64, P = 0.01), increased total protein levels in cerebrospinal fluids (0.76 ± 0.41 g/L vs. 0.56 ± 0.25 g/L, P = 0.002), and increased detection rates of brain magnetic resonance imaging abnormalities (72.22% vs. 44.90%, OR = 2.13, P = 0.039). The age at diagnosis of the symptomatic female patients (50.82 ± 9.31 years) was significantly higher than that of the asymptomatic female patients (42.30 ± 12.18 years, P = 0.038). The positive rate of TRUST in the cerebrospinal fluid samples was significantly higher in the patients with symptomatic neurosyphilis (55.93%) than in those with asymptomatic neurosyphilis (31.94%, OR = 2.70, P = 0.006), and so was the total protein level in cerebrospinal fluids (0.79 ± 0.46 g/L vs. 0.60 ± 0.24 g/L, P = 0.003) . Conclusion:The misdiagnosis rate of neurosyphilis is high at the first clinic visit; the condition of male patients is more serious than that of female patients; anti-syphilitic treatment history, gender and age may play some role in the development of neurosyphilis.

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