Lactobacillus rhamnosus GG ameliorates hyperuricemia in a novel model.

Hyperuricemia (HUA) is a metabolic syndrome caused by abnormal purine metabolism. Although recent studies have noted a relationship between the gut microbiota and gout, whether the microbiota could ameliorate HUA-associated systemic purine metabolism remains unclear. In this study, we constructed a novel model of HUA in geese and investigated the mechanism by which Lactobacillus rhamnosus GG (LGG) could have beneficial effects on HUA. The administration of antibiotics and fecal microbiota transplantation (FMT) experiments were used in this HUA goose model. The effects of LGG and its metabolites on HUA were evaluated in vivo and in vitro. Heterogeneous expression and gene knockout of LGG revealed the mechanism of LGG. Multi-omics analysis revealed that the Lactobacillus genus is associated with changes in purine metabolism in HUA. This study showed that LGG and its metabolites could alleviate HUA through the gut-liver-kidney axis. Whole-genome analysis, heterogeneous expression, and gene knockout of LGG enzymes ABC-type multidrug transport system (ABCT), inosine-uridine nucleoside N-ribohydrolase (iunH), and xanthine permease (pbuX) demonstrated the function of nucleoside degradation in LGG. Multi-omics and a correlation analysis in HUA patients and this goose model revealed that a serum proline deficiency, as well as changes in Collinsella and Lactobacillus, may be associated with the occurrence of HUA. Our findings demonstrated the potential of a goose model of diet-induced HUA, and LGG and proline could be promising therapies for HUA.

Anterior cingulate cortex orexin signaling mediates early-life stress-induced social impairment in females.

Early-life stress has long-term impacts on the structure and function of the anterior cingulate cortex (ACC), and raises the risk of adult neuropsychiatric disorders including social dysfunction. The underlying neural mechanisms, however, are still uncertain. Here, we show that, in female mice, maternal separation (MS) during the first three postnatal weeks results in social impairment accompanied with hypoactivity in pyramidal neurons (PNs) of the ACC. Activation of ACC PNs ameliorates MS-induced social impairment. Neuropeptide Hcrt, which encodes hypocretin (orexin), is the top down-regulated gene in the ACC of MS females. Activating ACC orexin terminals enhances the activity of ACC PNs and rescues the diminished sociability observed in MS females via an orexin receptor 2 (OxR2)-dependent mechanism. Our results suggest orexin signaling in the ACC is critical in mediating early-life stress-induced social impairment in females.

T-type Ca2+ channels and inward rectifier K+ channels contribute to the orexin-induced facilitation of GABAergic transmission onto pyramidal neurons in the prefrontal cortex of juvenile mice.

Orexin is a neuropeptide restrictedly synthesized in the hypothalamus, but extensively modulates the whole brain region activity including prefrontal cortex (PFC), and involved in the pathophysiology of psychiatric disorders. GABAergic interneurons in the mPFC are a promising pharmacological target for developing antidepressant therapies. Here, we examined the effects of the orexin on GABAergic transmission onto pyramidal neurons in the deep layers of the mPFC. We found that bath application of orexin dose-dependently increased the amplitude of evoked IPSCs (eIPSCs). Orexin increased the frequency but not the amplitude of miniature IPSCs (mIPSCs). Ca2+ influx through T-type voltage-gated Ca2+ channels is required for orexin-induced increases in GABA release. We also found orexin increases GABA release probability and the number of releasable vesicles. Orexin depolarizes somatostatin (Sst) interneurons without effects on the firing rate of action potentials (APs) of Sst interneurons. Orexin-induced depolarization of Sst interneurons is independent of extracellular Na+, Ca2+ and T-type Ca2+ channels, but requires inward rectifier K+ channels (Kirs). The present study suggests that orexin enhances GABAergic transmission onto mPFC pyramidal neurons through inhibiting Kirs on Sst interneurons, which further depolarizes interneurons leading to increase in Ca2+ influx via T-type Ca2+ channels. Our results may provide a cellular and molecular mechanism that helps explain the physiological functions of orexin in the brain.

Activation of metabotropic glutamate receptor 1 regulates hippocampal CA1 region excitability in rats with status epilepticus by suppressing the HCN1 channel.

Dysregulation of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels alters neuronal excitability. However, the role of HCN channels in status epilepticus is not fully understood. In this study, we established rat models of pentylenetetrazole-induced status epilepticus. We performed western blot assays and immunofluorescence staining. Our results showed that HCN1 channel protein expression, particularly HCN1 surface protein, was significantly decreased in the hippocampal CA1 region, whereas the expression of HCN2 channel protein was unchanged. Moreover, metabolic glutamate receptor 1 (mGluR1) protein expression was increased after status epilepticus. The mGluR1 agonist (RS)-3,5-dihydroxyphenylglycine injected intracerebroventricularly increased the sensitivity and severity of pentylenetetrazole-induced status epilepticus, whereas application of the mGluR1 antagonist (+)-2-methyl-4-carboxyphenylglycine (LY367385) alleviated the severity of pentylenetetrazole-induced status epilepticus. The results from double immunofluorescence labeling revealed that mGluR1 and HCN1 were co-localized in the CA1 region. Subsequently, a protein kinase A inhibitor (H89) administered intraperitoneally successfully reversed HCN1 channel inhibition, thereby suppressing the severity and prolonging the latency of pentylenetetrazole-induced status epilepticus. Furthermore, H89 reduced the level of mGluR1, downregulated cyclic adenosine monophosphate (cAMP)/protein kinase A expression, significantly increased tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) (1a-4) expression, and restored TRIP8b (1b-2) levels. TRIP8b (1a-4) and TRIP8b (1b-2) are subunits of Rab8b interacting protein that regulate HCN1 surface protein.

[Changes of T Cell Subsets and Their Relationship with Clinical Features and Prognosis in Patients with Acute Leukemia].

OBJECTIVE: To analyze the relationship between T cell subsets and clinical data. METHODS: mononuclear cells were collected from 103 patients with acute leukemia (AL) and 28 healthy volunteers, and percentage changes of CD3+CD4+, CD3+CD8+ and CD4+ CD25+ Foxp3+ cell subsets were assayed by flow cytometory. Relationship between the T subsets and clinical features of the patients was analyzed. RESULTS: Ratio of CD3+ T cells decreased more significantly in patients with >50% blast cells than that in patients with <50% blast cells, while the ratio of Treg between the 2 groups was not significantly different. Treg increased more statistically significantly in the patients with CD34+ leukemia cell than that with CD34- leukemia cells. In constrast to the relationship between prognosis and immune cells in the patients from 3 groups (low, intermediate and high-risk group) it was found that Treg cells increased more significantly in high-risk group than that in low-risk group. By continuously monitoring immune cells in 18 patients, it was found that Treg cells gradually increased during the first 3 courses of chemotherapy, then began to decreased in the 4th course, finally approached gradually to the normal value in the 6th course, and this change correlated with the clinical remission after chemotherapy. Treg cell number in the patients with AL was significantly higher than that in healthy controls, and Treg cell number during the onset and recurrence was significantly higher than that in the period of complete remission (continuous remission for over 6 months). Compared with the changes of immune cell number between different types of disease, it was found that Treg cells were increased more significantly in acute myeloid leukemia (AML) than that in acute lymphoblastic leukemia (ALL). Proportion of Treg cells, Treg/CD4 decreased more significantly after the 1st course of chemotherapy in the group with complete remission (CR) than that in the group without CR. The complete remission rate and recurrence rate were 68.9% and 20% respectively in the group with >10% Treg cells, while the complete remission rate and recurrence rate were 85.7% and 7.69% respectively in the group with.<10% Treg cells. In comparison of the 6 recurrent patients with 32 patients with sustained CR, it was found that the ratio of Treg cells and Treg/CD4 was increased more significantly in the patients with relapse than that with CR and in control group. CONCLUSION: Dynamic change of Treg cells in the peripheral blood was closely related with clinical feature, recurrence and prognosis in the patients with acute leukemia.

[ARTICLE WITHDRAWN] Downregulation of SRC Kinase Signaling Inhibitor 1 (SRCIN1) Expression by MicroRNA-32 Promotes Proliferation and Epithelial-Mesenchymal Transition in Human Liver Cancer Cells.

THIS ARTICLE WAS WITHDRAWN BY THE PUBLISHER IN NOVEMBER 2020.

Downregulation of SATB1 increases the invasiveness of Jurkat cell via activation of the WNT/ß-catenin signaling pathway in vitro.

Special AT-rich sequence-binding protein-1 (SATB1) is critical for genome organizer that reprograms chromatin organization and transcription profiles, and associated with tumor growth and metastasis in several cancer types. Many studies suggest that SATB1 overexpression is an indicator of poor prognosis in various cancers, such as breast cancer, malignant cutaneous melanoma, and liver cancer. However, their expression patterns and function values for adult T cell leukemia (ATL) are still largely unknown. The aim of this study is to examine the levels of SATB1 in ATL and to explore its function and mechanisms in Jurkat cell line. Here, we reported that SATB1 expressions were decreased in ATL cells (p < 0.001) compared with normal controls. Knockdown of SATB1 expression significantly enhanced invasion of Jurkat cell in vitro. Furthermore, knockdown of SATB1 gene enhances ß-catenin nuclear accumulation and transcriptional activity and thus may increase the invasiveness of Jurkat cell through the activation of Wnt/ß-catenin signaling pathway in vitro.

[HBeAg seroconversion achieved by sequential peginterferon alfa-2a therapy in chronic hepatitis B patients with unsatisfactory end point following entecavir treatment].

OBJECTIVE: To investigate the efficacy and safety of peginterferon alfa-2a (Peg-IFNa-2a) therapy for treating chronic hepatitis B (CHB) in patients who failed to achieve a satisfactory end point with entecavir (ETV) treatment. METHODS: Fifty-seven CHB patients with positivity for hepatitis B e antigen (HBeAg) who had completed a standard ETV monotherapy course, of at least 96 weeks, and who had achieved a virological response (defined as HBV DNA less than 500 copies/ml) but without HBeAg seroconversion (defined as 0.227 PEI U/ml less than HBeAg less than or equal to 50 PEI U/ml) were enrolled in the study. The patients were randomly assigned to receive a 48-week treatment with Peg -IFNa-2a (experimental group, n = 27) or continued ETV therapy (control group, n = 30). Serum samples were collected from all patients for assessment of biochemical, virological and serological responses to treatment. Inter-group differences were statistically evaluated by t-test or Chi-squared test. RESULTS: The baseline levels of alanine aminotransferase, hepatitis B surface antigen (HBsAg), and HBeAg were similar between the patients comprising the experimental and controls groups. At treatment week 48, the experimental group showed significantly higher rates of HBeAg clearance (Peg-IFNa-2a: 40.7% vs. ETV: 16.7%, x2 = 4.079, P less than 0.05) and seroconversion (37.0% vs. 13.3%, x2 = 5.110, P less than 0.05). The experimental group also showed higher rates of HBsAg clearance (7.4% vs. 0%) and HBV DNA relapse (11.1% vs. 0%), but the differences did not reach statistical significance (x2 = 2.307 and 3.519, both P more than 0.05). However, the level of HBsAg was significantly lower in the experimental group (2866.0+2580.4 vs. 4335.8+2650.0 IU/ml, t = 5.11, P less than 0.05). CONCLUSION: HBeAg-positive CHB patients with unsatisfactory response to initial ETV monotherapy achieved HBeAg seroconversion and clearance following sequential Peg-IFN a-2a treatment.

The Management of Membranous Glomerulopathy in Allogeneic Stem Cells Transplantation: Updated Literature

BACKGROUND: membranous glomerulopathy (MG) is an immunomediated disorder which accounts for the most common cause of nephrotic syndrome (NS) following allogeneic hematopoietic stem cell transplantation (HSCT). OBJECTIVE AND METHODS: to provide an update on the issue by reviewing pertinent literature on the MEDLINE database. RESULTS: sixty-nine post allogenic HSCT patients (42 male) with MG were identified. The median age was 43 (5 to 68) years. Time interval from allogenic HSCT to MG diagnosis ranged from 3 to 134 months (median 17). Most MG patients had a history of acute (70%) or chronic (84%) graft versus host disease (GVHD). Corticosteroids and cyclosporine were the most common therapeutic agents used in this setting; alternative therapies, including rituximab, were given to a lower number of patients. Outcome data were available in 64 out of 69 MG patients; 38 (59%) and 18 (28%) patients achieved a complete and a partial response respectively, whereas treatment failure was recorded in the remaining 8 (13%). CONCLUSION: MG after allogenic HSCT appears to be associated with a sub clinical or overt cGVHD, which follows the discontinuation of immunosuppressive prophylaxis. Although a standard therapeutic approach has not been established, the application of available measures can induce favorable response in more than 80% of affected patients, but treatment-failure and progressive deterioration of the renal function may occur in about one fifth of cases.

[Prevalence and clinical characteristics of thyroid disease induced by chronic hepatitis B treated with polyethylene glycol (peg) interferon-alpha].

OBJECTIVE: To study the prevalence and clinical characteristics of thyroid disease induced by chronic hepatitis B treated with polyethylene glycol (peg) interferon-alpha. METHODS: Totally 210 patients with chronic hepatitis B were monitored for thyroid function and thyroid antibodies before application of polyethylene glycol (peg) interferon-alpha therapy and every 3 months during and after the treatment. RESULTS: After treatment with polyethylene glycol (peg) interferon-alpha, 6.7% (14/210) of patients had thyroid disease, in which 5.2% (11/210) had hyperthyroidism and 1.4% (3/210) had hypothyroidism. The proportion of the hyperthyroidism and hypothyroidism in women were 11.8% (6/51) and 3.9% (2/51), higher than 3.1% (5/159) and 0.6% (1/159) in male (P < 0.05). In women subjects, higher proportion of those who developed thyroid disease were positive for antibody against thyroid peroxidase (TPOAb) before treatment and positive for antibody against thyroid globulin (TgAb) during the treatment as compared with those who did not develop thyroid disease (P < 0.05). CONCLUSION: Patients with chronic hepatitis B treated with polyethylene glycol (peg) interferon-alpha therapy are prone to develop thyroid disease. Women positive for TPOAb and TgAb may be at increased risk for developing thyroid disease.

[Efficacy of lamivudine and adefovir de novo combination therapy or after mono-therapy in chronic hepatitis B patients].

To investigate the efficacy of 104 weeks of lamivudine (LAM) and adefovir (ADV) de novo combination therapy, as compared to optimized combination therapy administered after 48 weeks of treatment with lamivudine or adefovir mono-therapy, in chronic hepatitis B (CHB) patients. A total of 174 patients with CHB were equally divided among three treatment groups: LAM mono-therapy; ADV mono-therapy; and LAM + ADV combination therapy. The patients in the LAM + ADV group were treated with LAM plus ADV for 104 consecutive weeks. The patients in the LAM or the ADV groups were first treated for 48 weeks with LAM or ADV, respectively, after which the patient's virological response was assessed. According to the results, the patient was continued on mono-therapy or switched to combination therapy for the subsequent 56 weeks. Virological and biochemical examinations were carried out at weeks 48 and 104. The rates of undetectable HBV DNA in the LAM mono-therapy, ADV mono-therapy, and LAM-ADV combination therapy groups at week 48 were 68%, 50%, and 84%, and at week 104 were 80%, 72%, and 95%, respectively. For the same groups, the virus breakthrough rates at week 48 were 15%, 0%, and 0%, and at week 104 were 18%, 2%, and 0%, respectively. Statistical analysis showed significant differences for the rate of undetectable HBV DNA between LAM + ADV group and LAM group at week 48 (x2 = 4.473, P= 0.034) and at week 104 (x2 = 5.795, P = 0.016), LAM + ADV group and ADM group at week 48 (x2 = 14.802, P less than 0.001) and week 104 (x2 = 5.547, P = 0.001). The hepatitis B e antigen (HBeAg) seroconversion rates at week 48 were 15% (x2 = 4.543, P = 0.033), 13% (x2 = 4.035, P = 0.045) and 38%, and at week 104 were 21% (x2 = 4.438, P = 0.035), 17% (x2 = 4.223, P = 0.04) and 44%, respectively, among patients positive for HBeAg. Statistical analysis showed that the differences among the three groups for each of these parameters were statistically significant (all, P less than 0.05). When compared with LAM or ADV mono-therapy followed by LAM+ADV at week 48, the LAM plus ADV de novo combination therapy for 104 weeks provided CHB patients with better virological and serological responses and a lower drug resistance rate.

[Study on the efficacy and HBeAg seroconversion related factors of telbivudine and entecavir therapy in HBeAg positive chronic hepatitis B patients].

OBJECTIVE: To investigate the efficacy of Telbivudine and Entecavir for therapy of HBeAg positive chronic hepatitis B for 52 weeks. METHODS: In this random and control study, the efficacy of Telbivudine and Entecavir treatments were compared in 180 patients with HBeAg positive chronic hepatitis B.The patients were randomly assigned to a daily 600 mg Telbivudine treatment group or daily 0.5 mg Entecavir group for 52 weeks. RESULTS: At week 52, HBV DNA undetectable rate was better in the Entecavir-treated group than in the Telbivudine-treated group, but didn't reach statistical significance. The viral breakthrough rates were significantly lower in the Entecavir-treated group than in the Telbivudine-treated group (x2 = 4.09, P <0.05). The clearance and seroconversion of HBeAg and the mean reductions of HBeAg from baseline at week 52 were significantly greater in the telbivudine-treated group than in the entecavir-treated group (x(2) clearance = 4.63, x(2) seroconversion = 4.80, (t-mean) reductions = 2.02; P < 0.05). The HBeAg seroconversion rates were not associated with both baseline ALT and baseline HBV DNA in both groups (P more than 0.05). In Telbivudine-treated group, the HBeAg decline is more than 2 log at week 24, HBeAg decline is more than 1 log at week 12 and the HBeAg baseline were independent factors correlated to HBeAg seroconversion rates at week 52 by Binary Logistic analysis, and also in entecavir-treated group the HBeAg decline is more than 2 log at week 24, HBeAg decline is more than 2 log at week 36 and the HBeAg decline is more than 2 log at week 12 were independent factors correlated to HBeAg seroconversion rates at week 52. CONCLUSION: Significant difference of HBeAg seroconversion rates at week 52 existed between Telbivudine-treated group and Entecavir-treated group. Entecavir is significantly superior to Telbivudine with less resistance to nucleosides. HBeAg decline is more than 2 log at week 24 is the best predicting factor for HBeAg seroconversion at week 52.

Nephrotic syndrome after allogeneic hematopoietic stem cell transplantation: etiology and pathogenesis.

In this study we investigated the etiology and pathogenesis of nephrotic syndrome (NS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 257 patients with hematopoietic malignancies who survived more than 2 months post allo-HSCT. Associations of NS with the conditioning regimen, graft versus host disease (GVHD), and other variables were analyzed. Pathologic features of the kidney, regulatory T cells (Tregs), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were studied. NS was identified in 9 patients. The number of Tregs at day+30, 60, 90, and 180 was lower in NS patients than non-NS patients (P=0.001, 0.001, 0.007, 0.003). Serum levels of IFN-γ and TNF-α were higher in NS patients (P=0.032, 0.001, respectively). NS post allo-HSCT was associated with the occurrence of chronic GVHD (P=0.02). NS post-HSCT is an immune disorder that may involve immune complex deposition, Th1 cytokines, and Tregs.

[Individualized respond guidance treatment of chronic hepatitis C with combination of peginterferon α-2a and ribavirin].

OBJECTIVE: To study individualized treatment of chronic hepatitis C (CHC) genotype 1 patients using respond guided therapy (RGT) of peginterferon α-2a in combination with ribavirin. METHODS: 140 patients with CHC genotype 1 received peginterferon α-2a 180 microg injection once a week in combination with ribavirin 800-1200 mg/d. Patients achieved RVR after 4 weeks treatment (group A) were randomized into 2 subgroups and proceeded with 24 and 48 weeks treatments (subgroups A1 and A2) respectively. Patients who had not received RVR but achieved cEVR at week 12 (group B) were further divided into 2 subgroups randomly and treated for 48 and 72 weeks (subgroups B1 and B2), respectively. Patients with PVR at week 24 were treated for 72 weeks (group C1), while patients without PVR at week 24 discontinued treatment (group C2). All Patients were followed-up for 24 weeks after the end of treatment. RESULTS: For patients treated for 24 weeks, the ETR rate was 100%, the SVR rate was 65.9%, and the relapse rate was 34.1%. For those treated for 48 weeks, the ETR, SVR and relapse rate were 95.3% , 82.8% and 12.5% respectively. For those treated for 72 weeks, the above rates were 82.1%, 67.9% and 14.3% respectively. SVR rates of subgroup A1 and A2 were 65.9% and 84.4% respectively and the difference was statistically significant (P<0.00). The HCV RNA loads were less than 1x10(6) copy/ml in group A and the SVR were 72.7% and 100% respectively with 24 and 48 weeks treatment, and the difference was insignificant statistically (P>0.05). SVR in subgroup B1 and B2 were 78.9% and 73.7% respectively and the difference was statistically insignificant (P>0.05). The SVR in group C1 was raised to 55. 6%. CONCLUSIONS: RVR and cEVR were respond guided prediction factors for CHC treatment. SVR among patients with RVR was higher in 48-week treatment than those with 24 weeks treatment. For patients with baseline virus load less than 1x10(6) copy/ml and achieved RVR, treatment duration can be shortened to 24 weeks. Treatment extension to 72 weeks can not result in SVR increase among patients without RVR but with cEVR. However, treatment extension to 72 weeks can increase SVR among those patients with PVR.

[Study on relationship between chemical castration and thymic function following hematopoietic stem cell transplantation].

OBJECTIVE: To evaluate the impact of luteinizing hormone-releasing hormone (LHRH) on the protection of thymic function after allogenic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Murine model of MHC mismatched allogeneic HSCT (C57BL/6-->BALB/c) was established. The severity of acute graft-versus-host-disease (GVHD) was assessed according to a clinical scoring system. The intra-cellular levels of IFN gamma, TNFalpha and IL-1 beta in thymocyte were analyzed by protein array and thymic function by quantification of signal-joint TCR rearrangement excision circles (sjTRECs). RESULTS: All recipients in group A (allogeneic mice), B (allogeneic LHRH castrated-mice) and C (syngenic mice) achieved hematopoietic reconstitution. White blood cell (WBC) over 1.0 x 10(9)/L in groups A, B and C were on day (11.2 +/- 1.4), day (9.8 +/- 0.6) and day (9.7 +/- 0.7), respectively (P = 0.003, 0.002). The onset of acute GVHD in group B was (14.1 +/- 0.7) d and in group A was (11.4 +/- 1.2) d (P = 0.000). All mice in groups A and B developed acute GVHD. No mice occurred aGVHD in group C. The average scores of acute GVHD in groups A and B were (9.1 +/- 0.7) and (5.1 +/- 1.0), respectively (P = 0.000). The levels of IFN gamma, TNFalpha and IL-1 beta in control group were (2.3 +/- 2.5) ng/ml, (1.7 +/- 1.1) pg/ml and (1.8 +/- 1.2) pg/ml, respectively. The IFN gamma levels in groups A, B and C were (10.5 +/- 2.1) ng/ml, (6.7 +/- 2.1) ng/ml and (5.2 +/- 3.3) ng/ml, TNFalpha levels were (7.0 +/- 2.6) pg/ml, (4.3 +/- 0.8) pg/ml and (3.0 +/- 1.8) pg/ml, and IL-1 beta levels were (24.9 +/- 9.0) pg/ml, (17.4 +/- 3.9) pg/ml and (10.8 +/- 3.1) pg/ml, respectively. There were significant differences in the levels of cytokines between group A and the control group (P = 0.000, 0.000, 0.000). The levels of cytokines in group B were significantly higher than those in control group (P = 0.000, 0.003, 0.000). The levels of IFN gamma and IL-beta in group C were significantly higher than those of in control group (P = 0.015, 0.013), and so did in group A than in group B (P = 0.002, 0.002, 0.004), and in group A than in group C (P = 0.000, 0.000, 0.000). The analysis of linear regression showed that the average levels of IFN gamma and TNFalpha paralleled with aGVHD scores (r(2) = 0.359, P = 0.045; r(2) = 0.228, P = 0.019). The average sjTRECs copies/1000 PBMNCs were (39.4 +/- 44.7) in the control group and (12.3 +/- 13.0), (58.0 +/- 71.8) and (19.6 +/- 14.6) in groups A, B and C, respectively. There was no significant difference in the multiple comparisons of peripheral blood levels of sjTRECs among these four groups (P = 0.468). CONCLUSION: IFN gamma, TNFalpha and IL-1 beta might be involved in the damage to the thymus by acute GVHD. Sex steroid inhibitor can not only reduce the severity of thymic damage after allo-HSCT, but also reduce the severity of aGVHD and the mechanism might be associated with the reduction of intra-cellular levels of IFN gamma in thymocyte.

Effect and mechanism of acute graft versus host disease on early diffuse murine lung injury following allogeneic stem cell transplantation.

To explore the effect and pathogenssis of acute graft-versus-host disease (aGVHD) on early diffuse lung injury in allogeneic hematopoietic stem cell transplantation (allo-HSCT), we established an aGVHD model of C(57)BL/6-->BALB/c mice. Chest computed tomography (CT) scans, histopathology and the levels of cytokines including tumor necrosis factor alpha (TNFalpha) and Interferon (IFNgamma) in lungs were dynamically detected in recipient mice after transplantation. The incidence of aGVHD was respectively 0%, 0% and 100% in simple irradiation group (A), syngeneic transplant group(B) and allogeneic transplant group (C). Chest CT scans of recipient mice were normal in 3 groups on days +3 and +7 after transplantation. CT showed that two of ten mice had bilateral lung diffuse infiltrate on day +12 (on the brink of death) in group A and 6 of 10 mice had bilateral lung diffuse infiltrate on day +14 (3 d after aGVHD occurring) in group C, and were normal on days +12 and +14 in group B after transplantation. Histopathology of lungs in the 3 groups was similar, consisting of minor interstitial pneumonitis on day +3. Group A showed edema, hyperplasia of epithelial cells and widened alveolar interval on day +7, and epithelial cell necrosis, lymphocyte infiltration, hemorrhage, protein leakage, and local consolidation on day +12. The histopathology of group B showed slight edema of epithelial cells on +7 day, which were slighter than that on day +3, and virtually normal on day +14. The histopathology in group C was characterized by the significant expansion and congestion of capillaries, and lymphocyte infiltration on day +7, the acute pneumonitis was present involving tissue edema, lymphocyte and macrophage infiltration, protein leakage and perivascular inflammation on day +14. In group A, the levels of TNFalpha were lower on day +7 than on day +3. In group B, the levels of TNFalpha attained a peak on day +3, which decreased on days +7 and +14. In group C, the levels of TNFalpha were highest on day +7 and there was a significant difference between those on days +7 and +14 (P=0.816). In group A, the levels of IFNgamma on day +7 were higher than on day +3. In group B, the levels of IFNgamma increased progressively, but the comparison of IFNgamma levels in different times had no statistical significance (P=0.521, 0.118, 0.340). In group C, the levels of IFNgamma attained a peak by day +7 and decreased on day +14. aGVHD is the main cause of early non-infectious lung injury. T lymphocytes and TNFalpha are possibly implicated in the pathogenesis of acute GVHD-induced lung injury. The decreased levels of IFNgamma in lung tissues following transplantation might be associated with pulmonary fibrosis in late non-infectious pulmonary complications.

[Association between acute graft versus host disease and lung injury after allogenic hematopoietic stem cell transplantation].

OBJECTIVE: To investigate the characteristics of chest high-resolution computed tomography (HRCT) and pathogenesis of acute graft versus host disease (aGVHD)-induced lung injury after allogenic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Chest HRCT was performed in 47 patients with aGVHD of grade II - IV after allo-HSCT. Twenty-four of the patients underwent different treatment regimens against aGVHD. Before the treatment peripheral blood samples were collected to detect the serum interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Transbronchial biopsy was performed in 4 patients that failed to recover completely after treatment. Pulmonary function was examined in the patients who survived more than 6 months in every 3 months. RESULTS: Twenty of the 47 patients showed abnormal images by chest HRCT and 17 of the 20 patients were suspected to be with aGVHD-induced lung injury. The HRCT images were characterized by diffused interstitial infiltrate in 5 cases, diffused interstitial and alveolar infiltrate in 7 cases, and diffused interstitial and segmental lobar alveolar infiltrate in 5 cases. Nine cases had bilateral pleural effusion and hydropericardium, including 4 cases accompanied by myocardial hypertrophy. The levels of serum IFN-gamma and TNF-alpha of the patients with lung injury were (6.9 +/- 1.8) microg/L and (400 +/- 102) microg/L respectively, both not significantly different from those of the patients without lung injury [(6.3 +/- 1.2) microg/L and (428 +/- 83) microg/L respectively, P = 0.202, 0.306]. The histopathology of the lung tissue was characterized by disorganization, epithelial cell damage, interstitial fibroplasia, and interstitial T lymphocyte or macrophage infiltrate. The effective rate of treatment for aGVHD-induced lung injury was positively correlated with that for aGVHD (r = 0.771, P = 0.01). Eleven of the 24 patients who survived more than 6 months had abnormal pulmonary function, including 7 out of the 9 patients with aGVHD-induced lung injury and 4 out the 15 patients without aGVHD-induced lung injury. There was no significant difference in the incidence of abnormal pulmonary function between the patients with and without lung injury (P = 0.033). CONCLUSIONS: Lung is one of the target organs of aGVHD. IFN-gamma and TNF-alpha may play a role in the pathogenesis of aGVHD-induced lung injury. Acute GVHD-induced lung injury may progress to late-onset non-infectious lung injury.

Association between acute graft versus host disease and lung injury after allogeneic haematopoietic stem cell transplantation.

OBJECTIVE: To investigate the characteristics of chest high-resolution computed tomography (HRCT) and pathogenesis of acute graft versus host disease (acute GVHD)-induced lung injury after allogeneic haematopoietic stem cell transplantation (allo-HSCT). METHODS: A study of 47 patients with acute GVHD of grades II-IV describes the clinical manifestations and characteristics of chest HRCT of acute GVHD-induced lung injury. Detection of serum interferon gamma (IFNgamma) and tumour necrosis factor alpha (TNFalpha) were performed before the treatment for acute GVHD. Transbronchial biopsy was performed in four patients whose chest HRCT did not recover completely after treatment for acute GVHD. Pulmonary function was measured in patients who survived more than 6 months in every 3 months. RESULTS: Chest HRCT scans were performed in 47 cases and 20 cases showed abnormal in which 17 cases were suspected of acute GVHD-induced lung injury. In 17 patients with acute GVHD-induced lung injury, HRCT revealed diffused interstitial infiltrate in five cases, diffused interstitial and alveolar infiltrate in seven cases, diffused interstitial and segmental lobar alveolar infiltrate in five cases accompanied by bilateral pleural effusion and hydropericardium in nine patients. There was no statistical significance between the levels of serum IFNgamma and TNFalpha in cases with and without lung injury, but the levels of serum IFNgamma and TNFalpha in patients were significantly higher than the healthy group (IFNgamma: p=0.000, TNFalpha: p=0.000). The histopathology of the lung tissue was characterized by disorganization, epithelial cell damage, interstitial fibroplasias and interstitial T lymphocyte or macrophage infiltrate. Forty-seven cases all attained the treatment for acute GVHD, and the total effective rate and the rate of completely remission (CR) were 74.47 and 55.32%, respectively. The total effective rate and the rate of CR in the treatment for acute GVHD-induced lung injury were 94.12 and 58.82%, respectively. The effective rate of treatment for acute GVHD-induced lung injury positively correlated with that for acute GVHD (r=0.771, p=0.001). Three cases in nine cases with lung injury and three cases in 15 cases without lung injury who survived more than 6 months developed late-onset non-infectious lung injury. Eleven patients of 24 patients who survived more than 6 months had abnormal pulmonary function, including seven patients in nine patients with acute GVHD-induced lung injury and four patients in 15 patients without acute GVHD-induced lung injury. There was no difference in the incidence of late-onset non-infectious lung injury, but significance in the incidence of abnormal pulmonary function between cases with and without lung injury (p=0.033, cross-tabs). CONCLUSIONS: These results suggested that the lung might be one of the target organs of acute GVHD and participation of T lymphocyte, macrophage and cytokines such as IFNgamma and TNFalpha might play a role in the pathogenesis of acute GVHD-induced lung injury. Acute GVHD-induced lung injury may progress to late-onset non-infectious lung injury.

[A clinical analysis of severe cyclosporine A-related neurotoxicity after allogenic hematopoietic stem cell transplantation].

OBJECTIVE: To investigate the morbidity, clinical manifestations, and imageology characteristics, and the influencing factors of severe cyclosporine A (CsA)-related neurotoxicity (SNCT) in the patients after allogenic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Finding of SNCT was carried out in 164 allo-HSCT recipients from January 2003 to June 2006. Clinical characteristics were analysed, including precursory symptoms and clinical manifestations. Associations between the onset of SNCT with blood CsA levels, age, transplant types, human leucocyte antigen (HLA) matching, conditioning regimens, antihuman thymocyte globulin (ATG) used in the prevention and treatment for graft-versus-host disease (GVHD) and intravenous corticosteroid used for acute GVHD were analyzed. Statistical analysis was performed with Binary Logistic Regression using SPSS/PC version 11.0. RESULTS: Thirteen patients (7.93%) were identified to have SNCT, including seizures (n = 8, 4.88%), paralysis (n = 6, 3.66%), coma (n = 2, 1.22%), cerebellar ataxia (n = 3, 1.83%) and chondroid encephalomyopathy (n = 1, 0.61%). All the patients had precursory symptoms prior SNCT including headache (n = 8), agitation (n = 4) and hypertension (n = 6). Magnetic resonance imaging (MRI) performed in twelve patients after SNCT showed that eleven patients had signal abnormalities in cerebral cortex and cerebral white matter. Six patients examined with computerized tomography (CT) had no abnormal findings. After extenuation or withdrawal of CsA, ten patients had complete recovery, two had partial recovery and one died of SNCT. Simple effect analysis of Binary Logistic Regression showed that the associations between the onset of SNCT with blood CsA levels, transplant types, HLA matching, ATG used in the prevention and treatment for GVHD and intravenous corticosteroid used for acute GVHD were of statistical significance. The multiple effect analysis of Binary Logistic Regression showed that the associations of the onset of SNCT with blood CsA levels and ATG used had statistical significance and the odds ratio (OR) was 1.007 (P = 0.006) and 6.727 (P = 0.030), respectively. CONCLUSIONS: 91.67% of the allo-HSCT recipients with SNCT have MRI abnormalities. High blood CsA levels and the use of ATG can elevate the risk of the occurrence of SNCT.

[Epstein-Barr virus-associated pneumonia in patients with post-transplant lymphoproliferative disease after hematopoietic stem cell transplantation].

OBJECTIVE: To investigate the clinical features of Epstein-Barr virus (EBV) reactivation or infection-induced post-transplant lymphoproliferative disease (PTLD) and EBV-associated pneumonia after hematopoietic stem cell transplantation (HSCT). METHODS: The clinical data of 7 patients with PTLD, 6 from the 239 patients undergoing allo-HSCT and 1 from the 84 patients undergoing auto-HSCT, were analyzed. RESULTS: All the 7 patients had extravisceral lymph node enlargement as the primary presentation. Five cases were diagnosed as with diffuse large B-cell lymphoma, 1 case as with polymorphic B-cell hyperplasia, and 1 case peripheral T-cell lymphoma-unspecified. Sex chromosome analysis showed that the tumor cells originated from the donors. ELISA showed that plasma EBV DNA was positive in 6 of the 7 patients and was negative in 1 patient. Chest CT revealed multifocal patches and diffuse ground-glass attenuation in both lungs. EBV-DNA was positive in the bronchoalveolar lavage (BAL) fluid. The T cells in all of the BAL fluid were mainly CD3+ T cells without CD19+ and CD20+ B cells. Lung biopsy showed interstitial and intra-alveolar infiltration, constituted mainly by CD3+ T cells and partly by CD68+ macrophages, however, without CD19+ and CD20+ B cells. The 3 patients with PTLD accompanied by EBV associated-pneumonia had hyperpyrexia and dyspnea, and their condition aggravated rapidly and eventually all the 3 patients died of respiratory failure, of which 1 case with multiple organ failure died within 2 weeks since the onset of PTLD. CONCLUSIONS: EBV-associated PTLD accompanied by EBV-associated pneumonia is not rare and is always severe. Cytology of BAL fluid and lung biopsy help diagnose.