OBJECTIVETo establish a new rat model of chronic cyclosporine A nephrotoxicity and explore its features.

METHODSTotally 24 male SD rats were equally randomized divided into 3 groups: sham-adrenalectomized (sham-ADX) group, ADX group and ADX plus cyclosporine A (CsA) group. Rats in ADX and CsA group first underwent adrenalectomy, followed by the administration of placebo or dexamethasone, respectively. Rats in sham-ADX group received sham adrenalectomy and distilled water as control. Six weeks later, all rats were sacrificed and the following indicators were evaluated: urine protein excretion, creatinine clearance, aldosterone level in serum and urine, aldosterone level and its synthase CYP11B2 gene expression in kidney, serum natrium and potassium, urine natrium and potassium excretion, and tubulointerstitial fibrosis by masson trichrome stain.

RESULTSIn ADX and CsA group, serum and urine aldosterone were undetectable on the second post-operative day, with other observations including natriuresis, hyponatremia, decreased urine potassium excretion, and hyperpotassemia, suggesting that adrenals were removed intact and the adrenalectomy was successful. Rats in CsA group showed increased urine protein, decreased creatinine clearance and tubulointerstitial fibrosis, suggesting that a model of chronic CsA nephrotoxicity was successfully established. At the endpoint, serum potassium, serum aldosterone, urine potassium and urine aldosterone excretion partially retrieved. Natrium in serum and urine was not significant different between ADX group/CsA group and sham-ADX group. Local renal aldosterone and its gene expression were remarkably upregulated.

CONCLUSIONSWe successfully established a new rat model of chronic CsA nephrotoxicity by adrenalectomy without low sodium diet. After adrenalectomy, local renal aldosterone in kidney may compensate for circulatory aldosterone deficit to maintain electrolyte balance.

Acute Kidney Injury ; chemically induced ; Adrenalectomy ; Aldosterone ; metabolism ; Animals ; Cyclosporine ; toxicity ; Disease Models, Animal ; Immunosuppressive Agents ; toxicity ; Kidney ; drug effects ; metabolism ; pathology ; Male ; Rats ; Rats, Sprague-Dawley

Aristolochic Acids ; adverse effects ; Child ; Drugs, Chinese Herbal ; adverse effects ; Female ; Humans ; Male ; Nephrosis ; chemically induced

Objective To investigate the clinical significance of velocity vector imaging(VVI)in evaluating the left ventricular(LV)segmental longitudinal systolic function in patients with coronary artery disease(CAD).Methods In 25 patients with myocardial ischemia,28 patients with myocardial infarction,26 patients with coronary lumen stenosis＜50%,according to coronary arteriography and electrocardiogram,the myocardial segments of LV were divided into 4 groups:ischemic segments group,infarcted segments group,non-ischemic segments group and normal segments group.Twenty-eight healthy subjects were selected as control group.Dynamic imaging of all subjects were collected,the systolic peak strain(Smax)and strain rate(SRmax),the time to peak strain(PTs)and the time to peak strain rate(PTsr)were measured respectively.Results Smax and SRmax of the ischemic segments and infracted segments were significantly lower than those of the control group respectively,PTs and PTsr of the ischemic segments and infracted segments were significantly longer than those of the control group respectively.Smax and SRmax of infarcted segments were significantly lower than those of the ischemic segments,there were no differences of PTs and PTsr between ischemic segments and infracted segments.Smax and SRmax cutoff of -14.08%,-0.83 s-1 for detecting ischemic segments and cutoff of -6.65%,-0.38 s-1 for detecting infracted segments,respectively,gave an optimal sensitivity and specificity.Conclusions VVI is a kind of novel noninvasive-tool to quantitatively assess LV regional systolic function in CAD patients.It is competent to differentiate between the ischemic segments and infarcted segments.

Biopsy ; Biopsy, Needle ; Bone Marrow ; pathology ; Bone Marrow Examination ; methods ; Bone Marrow Neoplasms ; pathology ; secondary ; Breast Neoplasms ; pathology ; Cytological Techniques ; Female ; Humans ; Lung Neoplasms ; pathology ; Male ; Prostatic Neoplasms ; pathology ; Retrospective Studies ; Stomach Neoplasms ; pathology

Objective To explore the relationship of polymorphisms of D17S1878, D17S932 sites and essential hypertension.Methods Sixty-seven pedigrees were collected at the region with high prevalence of hypertension. The polymorphisms of D17S1878 and D17S932 sites were genotyped using Genetic Analyzer and GeneScan Software. Case-control study in sibs with different phenotype was carried out and logistic analysis was used for multivariate analysis. Results There were significant differences on the distributions of age, male, drinking, average systolic pressure, average diastolic pressure, the characteristics of rash, body mass index (BMI), total cholesterol amount, triglyceride, low density lipoprotein(LDL) between the hypertensive-affected sibs and the normotensive sibs (P＜0.05). There was significant difference between the affected hypertensive and normotensive sibs in the D17S1878 site (P＜0.05), while there was no significant difference in D17S932 (P＞0.05 ). After non-conditional logistic analysis, data showed that both sites were not included in the model, while age( OR = 1.044,95%CI:1. 019-1. 069), drinking ( OR = 2. 644,95% CI : 1. 778-3. 932), the characteristics of rash ( OR = 3. 078,95%CI:1.721-5.504), triglyceride (OR= 1.305,95%CI: 1.016-1.676), LDL-C (OR= 1.787,95% CI:1. 296-2. 646), as risk factors, were included in the model. Conclusion The polymorphisms of D17S1878 and D17S932 possibly were not associated with essential hypertension.

Background: Congenital myasthenic syndromes (CMSs) are a group of clinically and genetically heterogeneous disorders caused by impaired neuromuscular transmission. The defect of AGRN was one of the causes of CMS through influencing the development and maintenance of neuromuscular transmission. However, CMS reports about this gene mutation were rare. Here, we report a novel homozygous missense mutation (c.5302G>C) of AGRN in a Chinese CMS pedigree. Methods: We performed a detailed clinical assessment of a Chinese family with three affected members. We screened for pathogenic mutations using a disease?related gene panel containing 519 genes associated with genetic myopathy (including 17 CMS genes). Results: In the family, the proband showed limb?girdle pattern of weakness with sparing of ocular, facial, bulbar, and respiratory muscles. Repetitive nerve stimulation showed a clear decrement of the compound muscle action potentials at 3 Hz only. Pathological analysis of the left tibialis anterior muscle showed predominance of type I fiber and the presence of scattered small angular fibers. The proband's two elder sisters shared a similar but more severe phenotype. By gene analysis, the same novel homozygous mutation (c.5302G>C, p.A1768P) of AGRN was identified in all three affected members, whereas the same heterozygous mutation was found in both parents, revealing an autosomal recessive transmission pattern. All patients showed beneficial responses to adrenergic agonists. Conclusions: This study reports a Chinese pedigree in which all three children carried the same novel AGRN mutation have CMS only affecting limb?girdle muscle. These findings might expand the spectrum of mutation in AGRN and enrich the phenotype of CMS.

BACKGROUNDShen song Yang xin (SSYX) is a compound of Chinese medicine with the effect of increasing heart rate (HR). This study aimed to evaluate its electrophysiological properties at heart and cellular levels.

METHODSThe Chinese miniature swines were randomly assigned to two groups, administered with SSYX or placebo for 4 weeks (n = 8 per group). Cardiac electrophysiological study (EPS) was performed before and after drug administration. The guinea pig ventricular myocytes were enzymatically isolated and whole cell voltage-clamp technique was used to evaluate the effect of SSYX on cardiac action potential (AP).

RESULTSSSYX treatment accelerated the HR from (141.8 +/- 36.0) beats per minute to (163.0 +/- 38.0) beats per minute (P = 0.013) without changing the other parameters in surface electrocardiogram. After blockage of the autonomic nervous system with metoprolol and atropin, SSYX had no effect on intrinsic HR (IHR), but decreased corrected sinus node recovery time (CSNRT) and sinus atrium conducting time (SACT). Intra cardiac EPS showed that SSYX significantly decreased the A-H and A-V intervals as well as shortened the atrial (A), atrioventricular node (AVN) and ventricular (V) effective refractory period (ERP). In isolated guinea pig ventricular myocytes, the most obvious effect of SSYX on action potential was a shortening of the action potential duration (APD) without change in shape of action potential. The shortening rates of APD(30), APD(50) and APD(90) were 19.5%, 17.8% and 15.3%, respectively. The resting potential (Em) and the interval between the end of APD(30) and APD(90) did not significantly change.

CONCLUSIONSThe present study demonstrates that SSYX increases the HR and enhances the conducting capacity of the heart in the condition of the intact autonomic nervous system. SSYX homogenously decreases the ERP of the heart and shortens the APD of the myocytes, suggesting its antiarrhythmic effect without proarrhythmia.

Action Potentials ; drug effects ; Animals ; Drugs, Chinese Herbal ; pharmacology ; Female ; Guinea Pigs ; Heart ; drug effects ; physiology ; Heart Rate ; drug effects ; Heart Ventricles ; In Vitro Techniques ; Male ; Myocytes, Cardiac ; drug effects ; physiology ; Sinoatrial Node ; drug effects ; physiology ; Swine ; Swine, Miniature

Cell Line ; Cyclic Nucleotide-Gated Cation Channels ; drug effects ; genetics ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; Electrophysiology ; Humans ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; Muscle Proteins ; drug effects ; genetics ; metabolism ; Potassium Channels ; Transfection

OBJECTIVETo investigate the effect of immature dendritic cells (inDC) genetically modified to express sTNFR I on acute graft-versus-host disease (aGVHD) and the graft-versus-leukemia (GVL) effect ofter allogeneic bone marrow transplantation (allo-BMT) in leukemic mice and its mechanism.

METHODSAn EL4 leukemia allo-BMT model was established with the BALB/c (H-2d) donor mice (DM)and C57BL/6 (H-2b) recipient mice (RM). The RM received DM bone marrow (BM) cells at a 1:1 ratio with spleen cells intravenously via tail vein at 4 h after TBI. Fifty DM were separated randomly into five groups: (1) Group A: total body irradiation (TBI) group, (2) Group B: lymphoma cell leukemia group, (3) Group C: allo-BMT group, (4) Group D: pXZ9-DC group, (5) Group E: sTNFR I-DC group. Acute GVHD scores, incidence of leukemic cell infiltration, histopathological analysis, survival rate, and survival rate of the recipients were estimated after allo-BMT. Enzyme-linked immunosorbent assay (ELISA) method was used to detect cytokines (INF-gamma and IL-4 ) production. Flow cytometry (FCM) analysis was used to detect allogeneic chimerism.

RESULTS(1) The mice in group A and group B all died of the BM failure and lymphoma cell leukemia, respectively. The mice in group C developed typical clinical signs of a GVHD after BMT with an average survival time(AST) of (11.50 +/- 3.50) d. The signs of aGVHD were less evident in the group D and E, and their AST (21.70 +/- 5.80 and 25.80 +/- 5.20 days, respectively) were all longer than that in group C (P < 0.05). AST of group E was the longest (P < 0.05). The mice in group B all died of leukemia within 18 days after engraftment of EL4 cells. There was was no significant difference in groups C, D and E in the incidence of leukemia (P > 0.05). (2) Serum IFN-gamma level reached peak value. At + 12 d, then decreased gradually in group C, D, and E, and then reached the nadir at +18 d post-BMT, with the lowest in group E (P < 0.05), and the level was significantly lower in group D than in group C (P < 0.05). After BMT, serum IL-4 level slightly decreased in group C, but gradually elevated in group D and E and reached their peak at +12 d, and even more significantly increased in group E (P < 0.05). There was no statistical significance in the pair wise comparison among three group (P < 0.05). (3) The average proportion of H-2d positive cells in RM was 95%-100% on day 30 post-BMT, with complete donor-type implantation.

CONCLUSIONImmature DC can induce immuno tolerance. Immature DC genetically modified to express sTNFR I has been shown to prevent acute GVHD in lethally irradiated mice reconstituted with allogeneic bone marrow grafts while maintaining the GVL response.

Animals ; Bone Marrow Transplantation ; adverse effects ; methods ; Dendritic Cells ; immunology ; Female ; Graft vs Host Disease ; prevention & control ; Graft vs Leukemia Effect ; Immune Tolerance ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Receptors, Tumor Necrosis Factor, Type I ; genetics ; Transplantation, Homologous

OBJECTIVETo study the characteristics of spectra on proton magnetic resonance spectroscopy (1H-MRS) and its value in patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS).

METHODSSeven clinically diagnosed patients with MELAS underwent magnetic resonance imaging (MRI) and 1H-MRS examinations. The 1H-MRS techniques, characteristics of the spectra, and its correlation with the laboratory tests were analyzed.

RESULTSCerebral abnormalities were revealed in all 7 patients on conventional MR images, and most abnormal signals were observed in bilateral occipital, parietal, and temporal lobes. We found 4 cases with basal ganglia involvement, 2 cases with mild frontal lobe lesions, and 1 case with involvement of lateral cerebral peduncles and thalami. Additionally, 1 patient was involved with left insular lobe. Spectra from prominent lesions in brain parenchyma showed lactate doublet peak in 6 patients, 3 of whom were also noted lactate peak in ventricular cerebrospinal fluid (CSF).

CONCLUSION1H-MRS may provide more direct information about the metabolism changes, which aids to affirm the diagnosis, and may replace the conventional invasive method of quantifying lactate in CSF.

Adolescent ; Adult ; Basal Ganglia ; pathology ; physiopathology ; Cerebral Cortex ; pathology ; physiopathology ; Child ; Female ; Humans ; Lactic Acid ; metabolism ; MELAS Syndrome ; diagnosis ; physiopathology ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Male ; Parietal Lobe ; pathology ; physiopathology