Tweety-homolog 1 (Ttyh1) is expressed in neural tissue and has been implicated in the generation of several brain diseases. However, its functional significance in pain processing is not understood. By disrupting the gene encoding Ttyh1, we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice, along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) in the basal state. More importantly, the peripheral inflammation-evoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice. Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release. Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief. Thus, in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.

BACKGROUND: The Shexiang Baoxin Pill (MUSKARDIA) has been used for treating coronary artery disease (CAD) and angina for more than 30 years in China. Nevertheless, methodologically sound trials on the use of MUSKARDIA in CAD patients are scarce. The aim of the study is to determine the effects of MUSKARDIA as an add-on to optimal medical therapy (OMT) in patients with stable CAD. METHODS: A total of 2674 participants with stable CAD from 97 hospitals in China were randomized 1:1 to a MUSKARDIA or placebo group for 24 months. Both groups received OMT according to local tertiary hospital protocols. The primary outcome was the occurrence of a major adverse cardiovascular event (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. Secondary outcomes included all-cause mortality, non-fatal MI, non-fatal stroke, hospitalization for unstable angina or heart failure, peripheral revascularization, angina stability and angina frequency. RESULTS: In all, 99.7% of the patients were treated with aspirin and 93.0% with statin. After 2 years of treatment, the occurrence of MACEs was reduced by 26.9% in the MUSKARDIA group (MUSKARDIA: 1.9% vs. placebo: 2.6%; odds ratio = 0.80; 95% confidence interval: 0.45-1.07; P  = 0.2869). Angina frequency was significantly reduced in the MUSKARDIA group at 18 months (P = 0.0362). Other secondary endpoints were similar between the two groups. The rates of adverse events were also similar between the two groups (MUSKARDIA: 17.7% vs. placebo: 17.4%, P = 0.8785). CONCLUSIONS: As an add-on to OMT, MUSKARDIA is safe and significantly reduces angina frequency in patients with stable CAD. Moreover, the use of MUSKARDIA is associated with a trend toward reduced MACEs in patients with stable CAD. The results suggest that MUSKARDIA can be used to manage patients with CAD. TRIAL REGISTRATION chictr.org.cn, No. ChiCTR-TRC-12003513.
Angina Pectoris ; China ; Coronary Artery Disease/drug therapy* ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Humans

OBJECTIVE: To investigate the charactcristics of CD180 expression and differentiation diagnostic value in B cell chronic lymphoproliferative disorders (B-CLPD) through detecting the mean fluorescence intensity（MFI）of CD180 in different sub types of B-CLPD，using multiparameter flow cytometry (FCM). METHODS: The CD180 MFI of malignant B cells in 178 patients with B-CLPD was detected by FCM. The level of CD180 MFI in various types of B-CLPD was compared to the normal control group. The level of CD180 MFI among sub-types of B-CLPD was also compared. RESULTS: (1) The expression levels of CD180 in B-CLPD was significantly lower as compared with the normal controls，except the spleen difuse red pulp lymphoma (SDRPL); (2) The CD180 MFI in chronic lymphocytic leukemia sCLL) was significantly lower as compared with other B-CLPD cells; (3) CD180 ware significantly overexpressed in HCL compared with MCL，LPL，and MZL (P <0.05); (4) In the spleen-derived B-CLPD，such as SMZL，HCL, HCL variation and SDRPL，the expression of CD180 has significant difference between lymphomas with or without villous. CONCLUSION Utilizing the multiparameter flow cytometry for defecting expression of CD180 and other immunological markers can more efficiently distinguish the subtypes of B-CLPD.
Antigens, CD ; analysis ; B-Lymphocytes ; Biomarkers ; Flow Cytometry ; Humans ; Immunophenotyping ; Leukemia, Lymphocytic, Chronic, B-Cell ; Lymphoproliferative Disorders

OBJECTIVETo explore the clinical efficacy and toxicity of CLAT protocol (cladribine, cytarabine and topotecan) for treating patients with refractory acute myeloid leukemia (R-AML).

METHODSA total of 18 patients with R-AML (median age 37 years, range 18 to 58 years; male n = 16, female n = 2) were treated with CLAT protocol, which consisted of cladribine 5 mg/m(2)/d, i.v. on days 1-5, cytarabine 1.5 g/m(2)/d, i.v. on days 1-5, topotecan 1.25 mg/m(2)/d, i.v. on days 1-5 and G-CSF 300 µg/d subcutaneous injection on day 6 until neutrophile granulocyte recovery.

RESULTSOut of 18 patients 2 died of severe infection before the assessment. Among 16 evaluated patients, 10 (55.6%) achieved complete remission (CR), and 2 (11.1%) achieved partial remission (PR), the overall response rate was 66.7%, the rest 4 patients did not respond (NR). The median overall survival time and DFS for the CR patients was 9.5 months (95%CI: 6.7-16.64) and 9.5 months (95%CI: 6.1-16.7) respectively. The 1 year OS and DFS rates were 45% and 46.9%, respectively. All patients developed grade 4 of granulocytopenia and thrombocytopenia, the median duration was 13 (range 2 to 21) days and 12 days (range 2 to 21), respectively, all patients developed infection, 2 patients died of severe infection. The most common non-hematological side effects included nausea, vomiting, diarrhoea, rash, aminotransferase or bilirubin elevation and were grade 1 to 2.

CONCLUSIONThe CLAT protocol seems to have promising for the treatment of refractory AML patients, and patients well tolerated. This CLAT protocol offers an alternative treatment for R-AML patients who received severe intensive treatment, especially with anthracycline-containing chemotherapy.

Adolescent ; Adult ; Agranulocytosis ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Cladribine ; therapeutic use ; Cytarabine ; therapeutic use ; Female ; Granulocyte Colony-Stimulating Factor ; therapeutic use ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; Male ; Middle Aged ; Remission Induction ; Thrombocytopenia ; Topotecan ; therapeutic use ; Young Adult

OBJECTIVETo investigate whether sodium valproate (VPA) directly regulates the activity of Ankyrin G(AnkG) promoter in vitro.

METHODSThe mouse AnkG promoter sequence was identified by comparing both human and mouse AnkG promoter sequences. The promoter was amplified from C57BL/6 mouse genome DNA and cloned into pGL3 Luciferase reporter vector. The Luciferase activity was detected in N2a and 293T cells and then treated with 0,0.5, and 1 mmol/L VPA for 12 h. The transcription activity of AnkG promoter in cells and the activity of VPA-treated Luciferase reporter vector in cells were detected using dual Luciferase reporter assay.

RESULTSThe AnkG promoter clone and its expression vector were successfully established, as confirmed by enzyme digestion and sequencing. The AnkG promoter showed high transcription activity in both N2a and 293T cells. The Luciferase activity was significantly induced following 0.5 mmol/L VPA treatment in both N2a and 293T cells. CONCLUSIONS VPA can up-regulate the AnkG expression via directly increasing its transcription activity. Thus, the in vivo AnkG expression may be directly regulated by the VPA at transcriptional level.

Animals ; Ankyrins ; Cell Line ; Genetic Vectors ; Humans ; Luciferases ; Mice ; Mice, Inbred C57BL ; Promoter Regions, Genetic ; Up-Regulation ; Valproic Acid

BACKGROUNDStroke occurs upon obstruction of cerebral blood circulation and is clinically characterized by sudden onset symptoms. Advanced age is the main risk factor of stroke, but cases of pediatric stroke have been rarely reported. This study aimed to determine the etiology, clinical presentation, and radiologic features of neurological deficit for pediatric arterial ischemic stroke (PAIS).

METHODSThe medical records of 42 PAIS patients (age range: 9 months to 13 years) treated at Wuhan Children's Hospital between July 2007 and January 2011 were retrospectively reviewed. Infarction location was first determined by craniocerebral computed tomography and magnetic resonance (MR) imaging. The stenotic or occluded main cerebral arteries and/or branches were determined by MR angiography and digital subtraction angiography.

RESULTSThe majority of the 42 PAIS cases (66.7%, n = 28) were ≤ 3 years old (vs. >3 years old: 33.3%, n = 14; P<0.05), but the male: female ratio was similar in both groups (P > 0.05). The most frequently reported signs and symptoms for both age groups were limited physical activity followed by convulsions and delirium, but convulsions were more prevalent in children ≤ 3 years-old. Children > 3 years-old mainly experienced the limited physical activity symptoms, including hemiparalysis, aphasia, and ataxia. For all 42 cases, the most frequent etiologies were infections (38.1%, n = 16), iron deficiency anemia (16.7%, n = 7), and moyamoya syndrome (11.9%, n = 5). The predominant infarcts among all cases were middle cerebral artery (63.6%, n = 21) and basal ganglia (64.3%, n = 27).

CONCLUSIONSPAIS occurs more frequently in younger children and this group most frequently presents with convulsion as the initial symptom. The overall etiologies of PAIS may be different from those of adult stroke and the involved regions may be distinguishing features of PAIS or its different forms, but more research is required.

Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Radiography ; Retrospective Studies ; Stroke ; diagnosis ; diagnostic imaging ; etiology

OBJECTIVETo study in vitro sperm damage caused by trichloroethylene in male rats.

METHODSSperms of Sprague-Dawley (SD) rats were collected 4 hours after being contaminated by trichloroethylene of 0, 2, 4, 6, 8, and 10 mmol/L in vitro. Giemsa staining was performed to observe the morphological changes of sperms, and flow cytometer was used to detect the changes in mitochondrial membrane potential.

RESULTSThe sperm motilities in 6, 8, and 10 mmol/L trichloroethylene groups decreased significantly compared with that in control group (P <0.01); the sperm aberration rates in 8 and 10 mmol/L trichloroethylene groups were significantly higher than that in control group (P<0.01). With the increase in exposure dose, the proportion of sperms with reduced mitochondrial membrane potential increased, and there were significant differences in sperm apoptosis rate between the 4, 6, 8, and 10 mmol/L trichloroethylene groups and control group (P<0.01).

CONCLUSIONIn vitro exposure to trichloroethylene can reduce sperm motility and increase the aberration rate and apoptosis rate of sperms in male SD rats.

Animals ; Apoptosis ; drug effects ; Male ; Membrane Potential, Mitochondrial ; drug effects ; Rats ; Rats, Sprague-Dawley ; Sperm Motility ; drug effects ; Spermatozoa ; cytology ; drug effects ; Trichloroethylene ; toxicity

OBJECTIVETo assess the efficacy and safety of Gastrosis No.1 compound in the treatment of functional dyspepsia with Spleen (Pi) and Stomach (Wei) deficiency-cold syndrome.

METHODSA randomized, double-blind, placebo-controlled trial was performed in 5 centers. Patients with functional dyspepsia (FD) of Spleen-deficiency and qi-stagnation syndrome (162 cases) were randomly assigned to groups given Chinese herbal medicine (CHM) Gastrosis No.1 compound or placebo in a 2:1 ratio. This trial included a 4-week treatment period and a 4-week follow-up period. The outcomes were the dyspepsia symptom scores (measured by total dyspepsia symptom scale and single dyspepsia symptom scale) and syndromes of traditional Chinese medicine score (measured by traditional Chinese medicine syndrome scale). The outcomes were noted at weeks 0, 4 and 8.

RESULTSCompared with patients in the placebo group, patients in the CHM group showed significant improvement in the dyspepsia symptom scores as rated by patients and investigators (P <0.01), and also showed improvement in syndromes of traditional Chinese medicine score (P <0.01). No serious adverse event was reported. Safety tests obtained after 4 weeks of treatment showed no abnormal values.

CONCLUSIONCHM Gastrosis No.1 compound was effective and safe in the treatment of functional dyspepsia with Spleen and Stomach deficiency-cold syndrome.

Adult ; Double-Blind Method ; Drugs, Chinese Herbal ; adverse effects ; pharmacology ; therapeutic use ; Dyspepsia ; drug therapy ; physiopathology ; Female ; Humans ; Male ; Placebos ; Spleen ; drug effects ; physiopathology ; Stomach ; drug effects ; physiopathology ; Syndrome ; Treatment Outcome

This study was aimed to investigate the c-kit mutation in acute myeloid leukemia (AML) patients with AML1-ETO and analyze its relation with clinical and laboratorial features and prognosis. PCR and sequencing methods were used to detect the c-kit 17 exon mutations in 31 AML patients with AML1-ETO. The relation of the c-kit mutation with clinical features, results of laboratorial examination and prognosis of disease were analyzed. The results showed that the c-kit mutation was found in 14 out of 31 AML patients and the mutation frequency was 45.16%. Male patients had a higher incidence of c-kit mutation than that of female patients (P = 0.020). The proportion of patients with newly diagnosed white blood cell>10×10(9)/L and with extramedullary infiltration in mutated group were higher than those in unmutated group respectively. No significant difference was observed at the age (P = 0.437) and the rate of bone marrow blasts(P = 0.510) between the above mentioned two groups. The difference in complete remission rate (64.29% vs 80%, P = 0.344)and relapse rate (58.33% vs 21.43%, P = 0.054) between c-kit mutated and c-kit unmutated groups were not significant. While the c-kit mutated group had a significant higher death rate as compared with c-kit unmutated group (57.14% vs 20%, P = 0.039). It is concluded that the c-kit mutation is frequent in AML patients with AML1-ETO and the c-kit mutated patients have a poor prognosis. It is important to detect c-kit mutation in routine clinical practice for patient's risk stratification, evaluation of prognosis and selection of effective treatment.
Adolescent ; Adult ; Aged ; Core Binding Factor Alpha 2 Subunit ; genetics ; DNA Mutational Analysis ; Female ; Humans ; Leukemia, Myeloid, Acute ; genetics ; pathology ; Male ; Middle Aged ; Mutation ; Oncogene Proteins, Fusion ; genetics ; Prognosis ; Proto-Oncogene Proteins c-kit ; genetics ; RUNX1 Translocation Partner 1 Protein ; Treatment Outcome ; Young Adult

The aim of this study was to investigate the renal function in 149 patients receiving myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) from June 2005 to June 2010 in our hospital, and analyze the risk factors resulting in kidney insufficiency and experience in diagnose and therapy. The creatinine clearance (CrCL) and serial creatinine level were evaluated before and after allo-HSCT within 100 days and 1 year. Non-radiation conditioning regimens were used for any patients. The acute kidney insufficiency (AKI) was defined as at least a 1.5-fold rise in serum creatinine level after allo-HSCT within the first 100 days. The chronic kidney insufficiency (CKI) was defined as the creatinine clearance < basal level within 3 months to 1 year after allo-HSCT. The results showed that the kidney insufficiency was found in 41 patients, in which the incidence of AKI was 32/149 (21.5%). CsA, amphotericin B (P = 0.025) and ES (P = 0.022) were defined as risk factors for AKI. The incidence of CKI was 18/138 (13%). cGVHD (P = 0.013) and TA-TMA (P = 0.012) were associated with the development of CKI. The 2-year survival was lower in patients with kidney dysfunction than that in patients without kidney dysfunction (39% vs 74.1%, P < 0.001). The main factors resulting in kidney insufficiency were defined as infection (52%), GVHD (20%), TA-TMA (12%) and tumor relapse (12%). It is concluded that kidney insufficiency is an important complication of allo-HSCT. Careful monitoring kidney function, minimizing the use of amphotericin B, prophylaxis and effective treatment of fungal infection, GVHD and TA-TMA may be effective preventive measures to decrease the incidence of kidney insufficiency.
Acute Kidney Injury ; etiology ; Adolescent ; Adult ; Female ; Hematopoietic Stem Cell Transplantation ; adverse effects ; Humans ; Male ; Middle Aged ; Renal Insufficiency ; etiology ; Retrospective Studies ; Risk Factors ; Transplantation, Homologous ; Young Adult