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Biomedical subjects

S Lu

Publications and source records attributed to S Lu.

At least 91 records · Page 5Linked to original sources

Recurrent chromosome changes in 62 primary gastric carcinomas detected by comparative genomic hybridization.

Comparative genomic hybridization (CGH) has been applied to detect recurrent chromosome alterations in 62 primary gastric carcinomas. Several nonrandom chromosomal changes, including gains of 8q (31 cases, 50%), 20q (29 cases, 47%) with a minimum gain region at 20q11. 2-q12, 13q (21 cases, 34%) with a minimum gain region at 13q22, and 3q (19 cases, 31%) were commonly observed. The regions most frequently lost included: 19p (23 cases, 37%), 17p (21 cases, 33%), and 1p (14 cases, 23%). High copy number gain (DNA sequence amplification) was detected in 6 cases. Amplification of 8q23-q24.2 and 20q11.2-q12 were observed in 3 cases. Gain of 20q and loss of 19p were confirmed by fluorescence in situ hybridization using corresponding bacterial artificial chromosomes (BAC) clones from those regions. The gain and loss of chromosomal regions identified in this study provide candidate regions involved in gastric tumorigenesis.

Adult↗

Non-transferrin-bound iron is present in serum of hereditary haemochromatosis heterozygotes.

BACKGROUND: Hereditary haemochromatosis (HH) is a common autosomal recessive disease. Recently, HH heterozygosity has been identified as an independent risk factor for myocardial infarction and cardiovascular mortality. Iron may play an important role in atherogenesis by catalyzing peroxidation of low-density-lipoprotein (LDL), an essential step in atherogenesis. In iron overload conditions, non-transferrin-bound iron (NTBI) is found in serum, which can catalyze lipid peroxidation. We investigated whether sera of HH heterozygotes contain more NTBI than sera of normal controls. METHODS: In 27 treated HH homozygotes, 22 HH heterozygotes and 17 healthy control subjects, conventional parameters of iron status (serum iron, transferrin saturation, serum ferritin) were measured. NTBI was detected using HPLC after addition of nitrilotriacetic acid and pretreatment with cobalt. RESULTS: The conventional parameters of iron status were similar in the HH heterozygous group and the control group. NTBI was significantly higher in homozygotes compared to heterozygotes (1.79 micromol L-1 vs. 0.51 micromol L-1, 95% CI of the difference = 0.6-1.95, P < 0.001), and controls (1.79 micromol L-1 vs. - 0.3 micromol L-1, 95% CI of the difference = 1.36-2.81, P < 0.001). The difference in NTBI between the heterozygous subjects and control subjects was also significant (0.51 micromol L-1 vs. - 0. 3 micromol L-1, 95% CI of the difference = 0.05-1.57, P < 0.05). CONCLUSION: Phlebotomy treated HH homozygotes maintain a high and potentially harmful serum NTBI. HH heterozygotes have a higher serum NTBI than normal controls. The reported increased risk of cardiovascular events in heterozygous haemochromatosis may be explained by NTBI-catalyzed LDL peroxidation.

Cardiovascular Diseases↗

Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized, placebo-controlled clinical trial.

BACKGROUND: Nasal challenge studies have suggested histamine and cysteinyl leukotrienes are important proinflammatory mediators in allergic rhinitis. This study was designed to determine the efficacy of montelukast, a cysteinyl leukotriene receptor antagonist, administered alone or concomitantly with loratadine, an H(1)-receptor antagonist, in seasonal allergic rhinitis. OBJECTIVE: The purpose of this study was to determine the effect of concomitant use of montelukast and loratadine in the treatment of seasonal allergic rhinitis. METHODS: In this multicenter (N = 12) double-blind, randomized, parallel-group, placebo-controlled 2-week trial, 460 men and women, aged 15 to 75 years, with spring seasonal allergic rhinitis were randomly allocated to receive 1 of the following 5 treatments: montelukast 10 or 20 mg, loratadine 10 mg, montelukast 10 mg with loratadine 10 mg, or placebo, once daily in the evening. The primary end point was daytime nasal symptoms score (average of congestion, rhinorrhea, itching, and sneezing). Other end points were eye symptoms, nighttime symptoms, individual daytime nasal symptoms, global evaluations (patient's and physician's), and rhinoconjunctivitis quality-of-life scores. RESULTS: Concomitant montelukast with loratadine improved the primary end point significantly (P <.001) compared with placebo and each agent alone. Compared with placebo, montelukast with loratadine also significantly improved eye symptoms, nighttime symptoms, individual daytime nasal symptoms, global evaluations, and quality of life. Montelukast alone and loratadine alone caused modest improvements in rhinitis end points. All treatments were similarly well tolerated. CONCLUSIONS: Concomitant montelukast with loratadine provided effective treatment for seasonal allergic rhinitis and associated eye symptoms with a safety profile comparable with placebo.

Acetates↗

The internal phosphodiesterase RegA is essential for the suppression of lateral pseudopods during Dictyostelium chemotaxis.

Dictyostelium strains in which the gene encoding the cytoplasmic cAMP phosphodiesterase RegA is inactivated form small aggregates. This defect was corrected by introducing copies of the wild-type regA gene, indicating that the defect was solely the consequence of the loss of the phosphodiesterase. Using a computer-assisted motion analysis system, regA(-) mutant cells were found to show little sense of direction during aggregation. When labeled wild-type cells were followed in a field of aggregating regA(-) cells, they also failed to move in an orderly direction, indicating that signaling was impaired in mutant cell cultures. However, when labeled regA(-) cells were followed in a field of aggregating wild-type cells, they again failed to move in an orderly manner, primarily in the deduced fronts of waves, indicating that the chemotactic response was also impaired. Since wild-type cells must assess both the increasing spatial gradient and the increasing temporal gradient of cAMP in the front of a natural wave, the behavior of regA(-) cells was motion analyzed first in simulated temporal waves in the absence of spatial gradients and then was analyzed in spatial gradients in the absence of temporal waves. Our results demonstrate that RegA is involved neither in assessing the direction of a spatial gradient of cAMP nor in distinguishing between increasing and decreasing temporal gradients of cAMP. However, RegA is essential for specifically suppressing lateral pseudopod formation during the response to an increasing temporal gradient of cAMP, a necessary component of natural chemotaxis. We discuss the possibility that RegA functions in a network that regulates myosin phosphorylation by controlling internal cAMP levels, and, in support of that hypothesis, we demonstrate that myosin II does not localize in a normal manner to the cortex of regA(-) cells in an increasing temporal gradient of cAMP.

3',5'-Cyclic-AMP Phosphodiesterases↗

Marking and gene expression by a lentivirus vector in transplanted human and nonhuman primate CD34(+) cells.

Recently, gene delivery vectors based on human immunodeficiency virus (HIV) have been developed as an alternative mode of gene delivery. These vectors have a number of advantages, particularly in regard to the ability to infect cells which are not actively dividing. However, the use of vectors based on human immunodeficiency virus raises a number of issues, not the least of which is safety; therefore, further characterization of marking and gene expression in different hematopoietic lineages in primate animal model systems is desirable. We use two animal model systems for gene therapy to test the efficiency of transduction and marking, as well as the safety of these vectors. The first utilizes the rhesus animal model for cytokine-mobilized autologous peripheral blood CD34(+) cell transplantation. The second uses the SCID-human (SCID-hu) thymus/liver chimeric graft animal model useful specifically for human T-lymphoid progenitor cell reconstitution. In the rhesus macaques, detectable levels of vector were observed in granulocytes, lymphocytes, monocytes, and, in one animal with the highest levels of marking, erythrocytes and platelets. In transplanted SCID-hu mice, we directly compared marking and gene expression of the lentivirus vector and a murine leukemia virus-derived vector in thymocytes. Marking was observed at comparable levels, but the lentivirus vector bearing an internal cytomegalovirus promoter expressed less efficiently than did the murine retroviral vector expressed from its own long terminal repeats. In assays for infectious HIV type 1 (HIV-1), no replication-competent HIV-1 was detected in either animal model system. Thus, these results indicate that while lentivirus vectors have no apparent deleterious effects and may have advantages over murine retroviral vectors, further study of the requirements for optimal use are warranted.

Animals↗

Anal verrucous carcinoma and penile condylomata acuminata.

A 50-year-old man presented with recurrent tumorous lesions on the penis and the anal region. The anal lesion was histologically diagnosed as verrucous carcinoma (VC) and the penile lesions were in line with condylomata acuminata. Samples taken from tumors of both sites were human papillomavirus (HPV) DNA positive. Two of them taken from the penis and the perianal region scored HPV DNA 6 positive by using polymerase chain reaction and the Southern blot method. Treatment of both VC and condylomata acuminata consisted in surgery and adjuvant immune therapy. Neither tumor recurrence nor metastases occurred up until 6 months after therapy.

Anus Neoplasms↗

Endothelin-dependent and -independent components of strain-activated brain natriuretic peptide gene transcription require extracellular signal regulated kinase and p38 mitogen-activated protein kinase.

The application of mechanical strain to cultured cardiac myocytes in vitro leads to activation of the brain natriuretic peptide (BNP) gene promoter, a marker of cardiac hypertrophy. We have previously shown that this activation results from both a direct mechanostimulatory event and an indirect autocrine/paracrine stimulation involving the sequential production of angiotensin II and endothelin (ET). In the present study, we examined the role of p38 mitogen-activated protein kinase (MAPK) and extracellular signal regulated kinase (ERK) in signaling the increase in promoter activity trafficking through each of these pathways. ET was shown to stimulate both p38 MAPK and ERK activity in these cultures and to activate human BNP (hBNP) promoter activity. Activation of the promoter was inhibited approximately 45% by SB-203580, a p38 MAPK inhibitor, and approximately 70% by PD98059, an inhibitor of the ERK-activating kinase MAPK kinase. The ET-independent (ie, direct) stimulation of the hBNP promoter by mechanical strain was inhibited approximately 70% by SB-203580 and approximately 60% by PD98059, implying that similar signaling circuitry is used, albeit to different degrees, by the direct and indirect pathways. The p38 MAPK component of both the ET-dependent and the ET-independent responses to strain appears to operate through a series of nuclear factor-kappaB binding, shear stress response element-like structures in the hBNP gene promoter. Collectively, these data suggest that activation of the BNP promoter by hypertrophic stimuli involves the participation of several independent signaling pathways. Such redundancy would help to guarantee generation of the full hypertrophic phenotype independently of the nature of the hypertrophic stimulus.

Animals↗

Molecular mechanisms of cell cycle block by methionine restriction in human prostate cancer cells.

Previous studies have shown that dietary or pharmacological methionine restriction inhibits growth of human prostate cancer cells in vitro or as xenografts in mice. We undertook the present studies to clarify the molecular mechanisms by which methionine restriction inhibits prostate cancer cell growth. We found that PC-3 and DU 145 cells stopped proliferating within six days in growth medium containing homocysteine in place of methionine. In contrast, proliferation of LNCaP cells was only partially inhibited by the absence of methionine. Using flow cytometry, we found that methionine restriction caused PC-3 cells to arrest in all phases of the cell cycle, but predominantly in the G2/M phase, whereas LNCaP cells accumulated exclusively in the G1 phase. Methionine restriction led to accumulation of the cyclin-dependent kinase inhibitors p21 and p27, as determined by Western blot analysis, and inhibited the enzymatic activities of the cyclin-dependent kinases CDK2 and cdc2, as determined by an in vitro kinase assay: However, methionine restriction had little or no effect on CDK2 or cdc2 protein levels. Methionine restriction also induced PC-3 cells to undergo apoptosis, as indicated by the appearance of a typical nucleosomal ladder on gel electrophoresis of genomic DNA. We conclude that methionine restriction has potential as a novel treatment strategy for prostate cancer.

Apoptosis↗

Androgen induction of cyclin-dependent kinase inhibitor p21 gene: role of androgen receptor and transcription factor Sp1 complex.

Previous studies have shown that androgen up-regulates expression of the p21 (WAF1, CIP1, SDI1, CAP20) gene, which contains a canonical androgen response element (ARE) in its proximal promoter region. We undertook the current studies to determine whether elements in the p21 promoter other than the ARE mediate androgen action. We found that deletion of the ARE did not completely abolish the promoter responsiveness to androgen, suggesting that additional cis-regulatory elements within the p21 core promoter may also be involved in androgen responsiveness. The p21 core promoter is GC-rich and contains six binding sites for transcription factor Sp1. We determined whether one or more of these Sp1 sites mediate androgen responsiveness of the p21 promoter. To do so, we used a transient transfection assay with p21 promoter-luciferase reporter constructs. The reporter activity of a construct lacking the ARE but containing all six Sp1 sites was induced approximately 3-fold by androgen. Mutation of Sp1-3 nearly eliminated basal promoter activity as well as androgen responsiveness, whereas deletion of Sp1-1 and Sp1-2 sites and mutation of Sp1-4, Sp1-5, and Sp1-6 sites had relatively little effect. We also used the mammalian one-hybrid assay and coimmunoprecipitation assay to show that androgen receptor (AR) and transcription factor Sp1 interact with one another. The current studies suggest a model in which AR and transcription factor Sp1 not only bind to their respective consensus sites within the p21 promoter, but also complex with one another, thereby recruiting coactivators and general transcription factors and inducing p21 transcription.

Adenocarcinoma↗

Morphometric analysis of the human ophthalmic nerve and the aging process.

In the present study, the morphometric changes that occur in the human ophthalmic nerve fibers during the aging process were analyzed with the use of new discriminative staining method, which permits simultaneous observation of the axon and surrounding myelin sheath. Morphometric data on axons were collected in 45 human cadavers. A significant reversed correlation was observed between those data and the age of the subject. Our results indicate that definite changes occur in the ophthalmic nerve during the aging process.

Aged↗

Dynamic contrast-enhanced T2-weighted MR imaging of recurrent malignant gliomas treated with thalidomide and carboplatin.

BACKGROUND AND PURPOSE: Dynamic, contrast-enhanced MR imaging has allowed quantitative assessment of cerebral blood volume (CBV) in brain tumors. The purpose of our study was to compare postcontrast T1-weighted imaging with dynamic, contrast-enhanced T2*-weighted echo-planar imaging in the evaluation of the response of recurrent malignant gliomas to thalidomide and carboplatin. METHODS: Serial MR imaging was performed in 18 consecutive patients with recurrent malignant gliomas receiving both thalidomide and carboplatin for 12-month periods. Six patients undergoing carboplatin therapy alone were chosen as control subjects. Conventional postcontrast T1-weighted images were compared with relative CBV (rCBV) maps calculated on a pixel-by-pixel basis from dynamic echo-planar imaging data. Tumor progression was evaluated clinically using established criteria for malignant gliomas. Studies were performed at 2- to 3-month intervals, and imaging and clinical findings were compared. RESULTS: Tumor response to treatment, based on clinical findings, did not correlate well with conventional imaging findings. The rCBV values decreased significantly in all patients between the start of therapy and the first follow-up in the study group, but not in the control group. The difference in rCBV values between the clinically stable and the progressive group at 12-month follow-up was statistically significant, with the progressive group having higher values. CONCLUSION: Dynamic, contrast-enhanced MR imaging is a valuable adjunct to conventional imaging in assessing tumor activity during antiangiogenic therapy, and correlates better than conventional studies with clinical status and response to therapy.

Adult↗

Association analysis of variants in the core promoter region of angiotensinogen gene with essential hypertension in Tibetan population.

OBJECTIVE: To detect the variants in the core promoter region of angiotensinogen(AGT) gene, and to analyse the relationship between the AGT gene polymorphisms and essential hypertension in Tibetan population. METHODS: This is a case-control study consisting of 103 essential hypertensive subjects and 82 normotensive controls matched by age and sex. The variants in the AGT gene core promoter region were screened by polymerase chain reaction/single strand conformation polymorphism(PCR/SSCP) and further identified by automated sequencing. The A(-6)G polymorphism was determined in DNA extracted from leucocytes by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). RESULTS: (1) There were two different electrophoresis band patterns in PCR/SSCP analysis. PCR product direct sequencing showed that the two band patterns represented the AA, AC genotypes in the (-20) site of AGT gene respectively. The distribution of A(-20)C genotype was almost identical in essential hypertensive and normotensive groups (P>0.8). The A allele frequency was very high in both groups (control: 0.9175, hypertensive: 0.9124). (2)Distribution of genotype in the (-6) site of AGT gene was much different between the patient group and control group (P<0.005). The frequency of G allele was statistically higher in the patient group than in controls (0.374 vs 0.220, P<0.025). CONCLUSION: Both Tibetan hypertensives and normotensives have higher frequency of A allele in AGT gene (-20) site. The higher frequency of G allele in the AGT gene (-6) site in Tibetan hypertension patients suggests that this allele may be the genetic susceptibility factor in the proceeding of essential hypertension in the Tibetan population.

Angiotensinogen↗

[Histological and ultrastructural characteristics of interface membrane around aseptically loosened prostheses].

OBJECTIVE: To investigate the effect of wear particles on prosthetic loosening by analyzing the histological and ultrastructural characteristics of interface membrane around aseptically loosened prostheses. METHODS: Slices of interface membranes around aseptically loosened hip prostheses of 51 cases were stained with HE, Safranin O-Briliant green and CD68 Mab immunohistochemical technique respectively. The histological structure of the membranes and the kinds of wear particles and their distribution characters were observed. The size of particles and the number of CD68 positive cells were measured. Ultrastructure of cells in the membrane and the characters and size of the particles phagocytozed by M phi were also observed and measured. RESULTS: Interface membrane consisted of fibromatrix, fibroblasts, M phi[CD68 positive, occupying (23 +/- 5)% (x +/- s)], and foreign body giant cells. In the membranes at the site of osteolysis, great amount of UHMWPE particles, PMMA particles and Ti alloy or CoCr alloy particles collected at the side attaching to the implant and caused chronic foreign body inflammatory reaction. Most of the particles outside M phi were less than 15 microns while that inside M phi were less than 1 micron. Different kinds of wear particles could exist in the lysosomes of one M phi. No particles but cartilage-like tisses appeared in the membranes at the site without osteolysis. CONCLUSION: Wear particles in the interface membrane have relations with osteolysis and fibrous tissue proliferation at bone-implant interface, which plays an important role in aseptic loosening.

Granuloma, Foreign-Body↗

Epidemiologic study of the irritable bowel syndrome in Beijing: stratified randomized study by cluster sampling.

OBJECTIVE: To explore the prevalence of irritable bowel syndrome (IBS) in Beijing and its risk factors. METHODS: Phase I: a screening for IBS in Beijing area according to symptoms using both Manning (modified including constipation) and Rome criteria. 2486 subjects were studied by cluster sampling of the inhabitant groups according to a stratified design of urban, suburban and rural areas, and sample size of each area studied was in proportion to the population of the area. Selection of the inhabitant groups was made by simple random sampling. Age of subjects enrolled in the study was 18-70 years. All subjects fulfilling the selection criteria were requested to fill in a questionnaire assisted by trained doctors or medical students during the visit to their families. Phase II: an aliquot of patients who fulfilled at least the Manning criteria were further selected according to their scoring series to undergo detail clinical examination in the hospital including laboratory examination, abdominal ultrasonography, colonoscopy or/and barium enema to exclude organic disease of the colon. Prevalence of IBS of the population was then adjusted by the rate of correct diagnosis during Phase II study. Study using Minnesota Multi-Personality Indices (MMPI) was done in some cases. Probable risk factors were explored by comparing their frequencies among IBS group and non-IBS group using chi 2 and logistic analysis of multifactors. RESULTS: The adjusted point prevalence of IBS in Beijing is 7.26% according to Manning criteria, and is 0.82% according to Rome criteria. There is a higher prevalence rate in city (10.50%) than in rural areas (6.14%) by stratified analysis (P < 0.001). Male to female ratio is 1:1.15. And IBS is more common in people aged between 18-40 years (51.6%), and among the intellectuals. Our study indicated that history of dysentery (OR 3.00), exposure to cool (OR 1.55) and ingestion of cold food and raw materials (OR 1.24) may be the most important risk factors (P < 0.001), and IBS patients may have a higher tendency of psychological abnormalities. CONCLUSION: IBS is a common disorder in Beijing and should be taken into consideration in the human welfare strategy.

Adolescent↗

[Growth inhibition effect of 5-aza-CdR on endometrial carcinoma xenografted in nude mice by p16 gene demethylation].

OBJECTIVE: To study the antitumor effect and mechanism of 5-aza-CdR on endometrial carcinoma xenografted in nude mice. METHODS: The effects of 5-aza-CdR on tumor growth inhibition were observed on human endometrial carcinoma xenografted in nude mice. The methylation status of the 5' CpG island of the p16 gene was evaluated using methylation-sensitive restriction enzymes and polymerase chain reaction. p16 mRNA expression was determined by reverse transcription-polymerase chain reaction. RESULTS: The inhibition rates of the tumor were 79.10% in 5-aza-CdR group (P < 0.01), 90.32% in 5-aza-CdR + DDP group (P < 0.01), and 10.13% in DDP group (P > 0.05), respectively, in comparison with control group. The methylation level of p16 gene was gradually decreased and the p16 mRNA expression restored after exposure to 5-aza-CdR. CONCLUSION: Our data show that 5-aza-CdR may inhibit tumor growth by reactivating growth-regulatory gene silenced by de novo methylation.

Animals↗

[Expression in E. coli of protein encoded by human esophageal cancer related gene-1].

OBJECTIVE: To express esophageal cancer related gene-1 (ECRG-1)--in E. coli. METHODS: The human ECRG-1 was cloned by RT-PCR. Expression plasmid of the ECRG-1/GST pi fusion gene was constructed and introduced into E. Coli. The fusion protein was induced to express by ITPG. The recombinant protein was identified by Western blot. BALB/C mice were immunized with the protein purified by SDS-PAGE for the preparation of polyclonal antibody. RESULTS: DNA sequencing confirmed that the sequence of ECRG-1 was identical to that of the previously obtained by 5'-RACE technique. Expression of the protein in E. coli was verified by Western blot. The polyclonal antibody obtained from immunized BALB/C mice had a title of 1:3,200. CONCLUSION: The antibody available is useful for the further study of structure and function of the esophageal cancer related protein.

Animals↗

[Methylation and expression of the p16 gene in endometrial carcinoma].

OBJECTIVE: To analyse the relationship between methylation status of the 5' CpG island and mRNA expression of the p16 gene in endometrial carcinoma. METHODS: Methylation status of p16 gene was determined by methylation-sensitive restriction enzymes, PCR and p16 mRNA expression was evaluated by RT-PCR in a series of 8 specimens with normal endometrium(NE), 6 with simple and complex hyperplasia(SCH), 6 with atypical hyperplasia (AH) and 38 with endometrial carcinoma(EC). RESULTS: Eight specimens of NE displayed no methylation and showed normal expression of the p16 mRNA. In 1 of the 6 AH and 13 of the 38(34.21%) EC, there was methylation of p16 exon 1; 5 of the 6 SCH showed overexpression of p16 mRNA, 4 of the 6 AH and 27 of the 38 (71.05%) EC exhibited decrease or loss of p16 mRNA expression. CONCLUSION: Hypermethylation of p16 gene is an early event of endometrial carcinogenesis and is associated with the progression of endometrial carcinoma. Hypermethylation is highly correlated with inhibition of p16 gene transcription.

Cyclin-Dependent Kinase Inhibitor p16↗

[Immunotherapeutic effect of Mycobacterium vaccae on multi-drug resistant pulmonary tuberculosis].

OBJECTIVE: To evaluate the immuNotherapeutic effect of M. vaccae on multi-drug resistant (MDR) pulmonary tuberculosis. METHODS: 90 cases of MDR pulmonary tuberculosis with bacteriological positive were divided into immunotherapy (M, 28 cases), control (C, 28 cases) group at random pair and self control (S, 34 cases) group. The group M were treated by chemotherapy and M. vaccae for 6 months, the group C only treated by chemotherapy for 6 months, while group S only by chemotherapy in the first 3 months and in combination with M. vaccae in the next 6 months. RESULTS: After 6 months, the sputum negative conversion rates of group M were 43% in smear positive cases and 46% in culture positive cases, both of which were significant higher than those of group C (21%, 18%, P < 0.01). The sputum negative conversion rates of group S were 3%, 3% in smear and culture positive cases after 3-month chemotherapy, which increased to 44%, 41% respectively when M. vaccae was added for 6 months. Compared with group C, group M was better in improving of X-ray manifestation and cell-mediated immunity and closing of cavity (P < 0.05). The bacteriological relapse rates in group M, C, S were 8%, 20% and 7% respectively. CONCLUSION: As a adjunct to chemotherapy, M. vaccae is helpful for patients with MDR pulmonary tuberculosis by improving the cell-medicated immunity, sputum negative conversion and X-ray manifestation.

Adult↗