[Relationship of diffusion kurtosis imaging parameters with the pathologic type and prognosis of rectal tumors].

Objective: To explore the application value of diffusion kurtosis imaging (DKI) in the differential diagnosis of rectal tumors and evaluating the prognostic factors associated with rectal adenocarcinoma. Methods: A total of 105 patients with rectal tumors admitted in the First Affiliated Hospital of Zhengzhou University from December 2018 to August 2020 were retrospectively analyzed. All patients underwent high-resolution magnetic resonance DKI scanning. The mean diffusivity (MD), mean kurtosis (MK) and apparent diffusion coefficient (ADC) were measured and the relationship of these parameters with pathological types and prognostic factors of rectal tumor were analyzed. The diagnostic efficacy of MD, MK, and ADC for positive circumferential resection margin (CRM) and extramural venous invasion (EMVI) of rectal adenocarcinoma was evaluated by the receiver operating characteristic (ROC) curve. Results: MD and ADC were only related to pathological type. The MD and ADC were (2.091±0.390)×10(-3) and (1.478±0.265)×10(-3) mm(2)/s in mucinous adenocarcinoma, higher than (1.136±0.182)×10(-3) and (0.767±0.077)×10(-3) mm(2)/s in unspecified adenocarcinoma and (1.617±0.697)×10(-3) and (0.940±0.179)×10(-3) mm(2)/s in tubulo-villous adenoma. The MD and ADC in unspecified adenocarcinoma were lower than those in tubule-villous adenoma (P<0.05). Nevertheless, MK was associated with pathological type, N stage, CRM and EMVI. The MK was 0.566±0.110 in mucinous adenocarcinoma, lower than 0.982±0.135 in unspecified adenocarcinoma and 0.827±0.121 in tubulo-villous adenoma. The MK in unspecified adenocarcinoma was higher than that in intubulo-villous adenoma. The MK was 0.984±0.107 in pN1-2, higher than 0.881±0.146 in pN0. The MK was 0.990±0.142 in positive CRM, higher than 0.862±0.114 in negative CRM. The MK was 0.996±0.140 in positive EMVI, higher than 0.832±0.100 in negative EMVI (P<0.05). The ROC curves showed that the AUCs of MD, MK and ADC in diagnosing positive CRM were 0.459, 0.653 and 0.408, respectively; with MK=1.006 as the optimal diagnostic threshold, the diagnostic sensitivity and specificity were 51.9% and 81.0%, respectively. The AUCs of MD, MK and ADC values in diagnosing positive EMVI were 0.510, 0.662 and 0.388, respectively; with MK=1.010 as the optimal diagnostic threshold, the diagnostic sensitivity and specificity were 50.9% and 87.5%, respectively. Conclusions: DKI quantitative parameter is helpful for discriminating rectal tubulo-villous adenoma, unspecified adenocarcinoma, and mucinous adenocarcinoma, and is helpful for predicting the prognosis of patients with rectal adenocarcinoma. High MK is associated with positive CRM and EMVI.

[Clinical characteristics of 272 437 patients with different histopathological subtypes of primary esophageal malignant tumors].

Objective: To characterize the histopathological subtypes and their clinicopathological parameters of gender and onset age by common, rare and sparse primary esophageal malignant tumors (PEMT). Methods: A total of 272 437 patients with PEMT were enrolled in this study, and all of the patients were received radical surgery. The clinicopathological information of the patients was obtained from the database established by the State Key Laboratory of Esophageal Cancer Prevention & Treatment from September 1973 to December 2020, which included the clinical treatment, pathological diagnosis and follow-up information of esophagus and gastric cardia cancers. All patients were diagnosed and classified by the criteria of esophageal tumor histopathological diagnosis and classification (2019) of the World Health Organization (WHO). The esophageal tumors, which were not included in the WHO classification, were analyzed separately according to the postoperative pathological diagnosis. The χ2 test was performed by the SPSS 25.0 software on count data, and the test standard α=0.05. Results: A total of 32 histopathological types were identified in the enrolled PEMT patients, of which 10 subtypes were not included in the WHO classification. According to the frequency, PEMT were divided into common (esophageal squamous cell carcinoma, ESCC, accounting for 97.1%), rare (esophageal adenocarcinoma, EAC, accounting for 2.3%) and sparse (mainly esophageal small cell carcinoma, malignant melanoma, etc., accounting for 0.6%). All the common, rare, and sparse types occurred predominantly in male patients, and the gender difference of rare type was most significant (EAC, male∶ female, 2.67∶1), followed with common type (ESCC, male∶ female, 1.78∶1) and sparse type (male∶ female, 1.71∶1). The common type (ESCC) mainly occurred in the middle thoracic segment (65.2%), while the rare type (EAC) mainly occurred in the lower thoracic segment (56.8%). Among the sparse type, malignant melanoma and malignant fibrous histiocytoma were both predominantly located in the lower thoracic segment (51.7%, 66.7%), and the others were mainly in the middle thoracic segment. Conclusion: ESCC is the most common type among the 32 histopathological types of PEMT, followed by EAC as the rare type, and esophageal small cell carcinoma and malignant melanoma as the major sparse type, and all of which are mainly occur in male patients. The common type of ESCC mainly occur in the middle thoracic segment, while the rare type of EAC mainly in the lower thoracic segment. The mainly sparse type of malignant melanoma and malignant fibrous histiocytoma predominately occur in the lower thoracic segment, and the remaining sparse types mainly occur in the middle thoracic segment.

[Assessment of MS-Score and HScore in timeliness of diagnosis of macrophage activation syndrome associated with adult-onset Still's disease].

The data of 33 patients with adult-onset still's disease (AOSD)-associated macrophage activation syndrome (MAS) were retrospectively collected from January 2013 to December 2020 in Peking Union Medical College Hospital. Hemophagocytic lymphohistiocytosis (HLH)-2004 criteria, macrophage activation syndrome/juvenile idiopathic arthritis (MS-Score) and hemophagocytic syndrome diagnostic score (HScore) were used to diagnose AOSD-associated MAS, respectively. The time of diagnosis of AOSD-associated MAS by MS-Score was 19.0 (4.5, 31.0) days [M (Q1,Q3)] earlier than by HLH-2004 criteria, and 13.5 (0.5, 21.5) days earlier than by HScore (both P<0.05). The difference was not statistically significant between the time of diagnosis of AOSD-associated MAS by Hscore and by HLH-2004 criteria (P>0.05). There was significant difference among the three criteria (P<0.001). MS-Score can be used to diagnose AOSD-associated MAS earlier than HLH-2004 criteria, while the timeliness of HScore is not certain.

[Mediated pathways of exosomes uptake by stem cells of apical papilla].

OBJECTIVE: To evaluate the uptake of exosomes by stem cells from apical papilla (SCAP), thus to provide experimental basis for mechanism of the exosomes endocytosis by SCAP. METHODS: (1) Exosomes of dental pulp stem cells (DPSCs) were isolated by hypercentrifugation combined with ultrafiltration method. The exosomes were identified by transmission electron microscopy, nanoparticle tracking analysis and western blot. (2) PKH-26 membrane labeling technology was used to mark the DPSCs derived exosomes. The labeled exosomes were co-cultured with SCAP at 37 °C as positive control group, and co-cultured with SCAP at 4 °C as the low-temperature treatment group, while the negative control group was set up. (3) Using clathrin-mediated endocytosis inhibitor chlorpromazine (CPZ, 10 µmol /L) as CPZ group, caveolae-mediated endocytosis Genistein (200 µmol/L) as Genistein group, and macropinocytosis inhibitor LY294002 (50 µmol/L) as LY294002 group to treat the SCAP respectively. Solvent control group (DMSO group) was set. Immunofluorescence staining was used to detect the red fluorescence SCAP and flow cytometry was used to analyze the proportion of SCAP labeled with red fluorescence. RESULTS: (1) The bilayer membrane and cup-shaped appearance of representative exosomes were observed. The peak of the size of DPSCs-derived exosomes was at 144 nm. The exosomes expressed exosomal marker proteins TSG101 and CD63, but not GAPDH which was the cellular internal control protein. (2) Immunofluorescence staining showed that after being co-cultured at 37 °C for 6 hours, red fluorescence could be detected in SCAP but it could not be detected after being co-cultured at 4 °C for 6 hours. After endocytosis inhibition, the red fluorescence in SCAP was reduced. Flow cytometry showed that the proportion of SCAP labeled with red fluorescence in positive group was 35.0%, in negative control group was 0.5%, and in solvent control group was 29.7%, in CPZ group, Genistein group and Genistein group were reduced to 13.7%, 16.6%, and 20.9%, respectively. CONCLUSION: SCAP could uptake the DPSCs derived exosomes, and low temperature could inhibit this process. The exosomes uptake of SCAP was mediated by the clathrin endocytosis pathway, caveolae-mediated endocytosis and macropinocytosis pathway.

[Anti-myelin-associated glycoprotein antibody positive IgM monoclonal gammopathy related peripheral neuropathy: 11 cases and literature review].

Objective: To improve the understanding of rare anti-myelin-associated glycoprotein (MAG) positive IgM monoclonal gammopathy related peripheral neuropathy (IgM-PN) . Methods: Eleven cases of IgM paraproteinemia and anti-MAG antibody positive neuropathy diagnosed since 2014 in Peking Medical Union College Hospital were summarized. The medical records including clinical manifestation, lab results, treatment and prognosis were analyzed. Results: Among the 11 patients (8 male and 3 female) , the median onset age is 63 years old (range from 52 to 77 years old) . The peripheral neuropathy of 9 patients were characterized by distal onset of numbness, 6 patients suffered from muscle weakness. The nerve conduction velocity study indicated that all 11 patients had demyelinating peripheral nerve damage, which was sensory predominant and more severe in lower limbs, 6 of them had secondary axonal damage. Monoclonal IgM gammopathy was identified in all 11 patients, among which 6 were IgM κ, 2 IgG κ and IgM κ bi-clonal, 3 IgM λ. Three patients were diagnosed with Waldenström's macroglobulinaemia. The anti-MAG-IgM antibody was positive in all 11 cases. After diagnosis, 9 patients received combination chemotherapy including rituximab or rituximab treatment alone. The monoclonal IgM level declined significantly in 7 patients. The neuropathy was stable or improved. Conclusions: Anti-MAG antibody positive IgM-PN is a rare M protein related disease. In peripheral neuropathy with undetermined etiology, we suggest to screen M protein and anti-MAG antibody. Chemotherapy including rituximab or rituximab alone is recommended as first-line therapy.

[Effect of oral appliance treatment on age-related changes of sleep respiratory function in patients with obstructive sleep apnea hypopnea syndrome].

Objective: The severity of obstructive sleep apnea hypopnea syndrome (OSAHS) has a tendency to increase with age. The purpose of this study was to explore whether oral appliance (OA) treatment can block this age-related change. Methods: This study was a retrospective study. Fifteen patients (12 males,3 females) of OSAHS treated with OA were selected as treatment group,with an average age of (47.44±10.00) years and initial body mass index (BMI) of (26.31±3.33) kg/m(2). The follow-up length was 54 [22, 100] months. Nineteen patients (13 males,6 females) with untreated OSAHS served as controls, with an average age of (45.00±9.26) years and initial BMI of (25.53±2.58) kg/m(2),and the follow-up length was 35 [26,63] months. There were no significant differences in terms of gender,age,initial BMI, apnea hypopnea index(AHI), and follow-up length between the two groups. Polysomnography(PSG) data for the two groups were compared to observe the sleep respiratory function changes as aging by Wilcoxon test. Results: There was no significant difference in BMI of the treatment group and the control group at the time of follow-up, with BMI of treatment group from (26.31±3.33) kg/m(2) to (25.67±3.65) kg/m(2),Z=-1.223,P=0.221; and BMI of control group from (25.53±2.58) kg/m(2) to (25.12±2.72) kg/m(2),Z=-1.193,P=0.233. There was no significant difference in the change of AHI within the treatment group, from 26.20 [11.50, 52.98]/h to 23.10 [16.00, 45.00]/h, Z=-0.284, P=0.776; AHI in the control group was higher than that at the first visit, and the AHI increased from 15.00 [10.72, 28.90]/h to 31.10 [13.00, 41.80]/h, Z=-3.481, P<0.001. The longest apnea duration was not statistically different in the treatment group, from 60.00 [56.40, 74.00] s to 63.00 [52.00, 77.00] s, Z=-0.345, P=0.730; the longest apnea duration in the control group increased from 42.00 [34.00, 56.70] s to 46.00 [37.00,62.00] s,Z=-2.274,P=0.023. There was no significant difference in the lowest blood oxygen saturation of the treatment group and the control group, with the treatment group from 72.47%±12.69% to 72.73%±17.59%, Z=-0.597, P=0.550; and the control group from 78.21%±9.30% to 76.42%±12.17%, Z=-0.153, P=0.879. Conclusion: Symptoms of sleep apnea in OSAHS patients tend to increase with age,and oral appliance treatment may have the effect of slowing down this age-related worsening effect.

Effects of heparin catheter-sealing solution for implantable venous access ports on D-dimer levels in older cancer patients.

OBJECTIVE: To investigate the effects of different concentrations of heparin catheter-sealing solution for implantable venous access ports (VAPs) on D-dimers (D-D) in older cancer patients. PATIENTS AND METHODS: A total of 208 older cancer patients who received intravenous chemotherapy for the first time were randomly divided into four groups: the normal saline group, the low concentration heparin group (25 U/ml), the medium concentration heparin group (50 U/ml), and the high concentration heparin group (75 U/ml), with 52 patients in each group. VAPs were sealed by the positive pressure technique every day before and after perfusion, as well as at the end of a course of chemotherapy when the butterfly needle was removed. The patients were followed-up for three courses of chemotherapy, and comparisons of the clinical effects were conducted. RESULTS: Before treatment and at the end of follow-up, no significant differences among groups were found in platelet count, prothrombin time, thrombin time, or activated partial thromboplastin time (p>0.05). At the end of follow-up, the high concentration heparin group had reduced fibrinogen (FIB) and increased D-D compared with the other groups, and the differences were statistically significant (p<0.05). The other three groups showed no significant differences in FIB or D-D before treatment or at the end of follow-up (p>0.05). The high concentration heparin group had higher local bleeding rate, while the saline group had higher partial and complete prevalence of blockage compared with the other groups. The differences were statistically significant (p<0.05). CONCLUSIONS: 25-50 U/ml heparin catheter-sealing solution had little effect on blood circulation and coagulation. Additionally, it did not increase the risk of local bleeding or thrombotic blockage.

[Nasopharyngeal changes in 8-13 years old healthy children in China: a longitudinal study].

Objective: Nasopharynx is an important compartment of the upper airway. It is closely associated with the characteristic craniofacial skeletal pattern related to sleep breathing. The present study aimed to investigate the growth pattern of the nasopharynx during rapid puberty growth period. Methods: Thirty non-snoring children (aged 8 to 11 years old) were selected by means of questionnaires and clinical examination. Periodic yearly follow up using MRI, lateral cephalogram, and polysomnograph (PSG) was done in these children. Fifty-one final mixed longitudinal samples were consisted of 23 children completed three consecutive follow-up, and 5 children completed two consecutive follow-up. The yearly changes of the nasopharynx and craniofacial structures were measured. ANOVA was used to evaluate the yearly growth of the nasopharynx. Correlated analysis was used to explore the potential influencing factors of craniofacial structures. Results: The rapid growth period of the nasopharynx located in the age range of 8-10 years old, during which the transverse dimension of the nasopharynx developed rapidly, while the rapid development of the sagittal dimension of the nasopharynx was around 12-13 years old. The growth of the nasopharynx was continuous. The changes in the cross-sectional area of the nasopharynx (⊿CSA) was positively correlated with the changes in distance between mandible of glossopharyngeus (⊿M), distance of hyoid to cervical anterior surface (⊿H-CVP), and anterior pharyngeal distance of glossopharyngeus (⊿AD) (r=0.363, 0.363, 0.323, respectively, all P<0.05). The changes in the volume of the nasopharynx (⊿V) was positively correlated with the changes in upper facial height (⊿N-ANS), ⊿M, and ⊿AD (r=0.336, 0.413, 0.478, respectively, all P<0.05). The changes in the sagittal dimension of the nasopharynx (⊿S) was negatively correlated with angulation in supramental and anatomical horizontal line (⊿SNB) (r=-0.322, P=0.045). The changes in the transverse dimension of the nasopharynx (⊿T) was negatively correlated with the changes in adenoid (⊿A) (r=-0.411, P=0.009). Conclusions: The growth and development of the nasopharynx was early and continuous, which could be affected by the development of either maxilla or mandible.

Downregulation of ZBTB24 hampers the G0/1- to S-phase cell-cycle transition via upregulating the expression of IRF-4 in human B cells.

It has been recently identified that loss-of-function mutations in the uncharacterized gene ZBTB24 (zinc finger and BTB domain-containing 24) cause ICF2 (immunodeficiency, centromeric instability and facial anomalies syndrome 2) with immunological characteristics of greatly reduced serum antibodies and circulating memory B cells. ZBTB24 belongs to the large ZBTB family of transcriptional repressors with members like B-cell lymphoma 6 (BCL-6; ZBTB27) playing critical roles in B-cell functions. Given the genotype-phenotype correlation analyses in ICF2 patients and the high expression of ZBTB24 in human B cells, we, in the present study, investigated the function of ZBTB24 in human B-cell line Raji cells. Knockdown of endogenous ZBTB24 by small hairpin RNAs results in a significantly reduced proliferation through blocking the G0/1- to S-phase cell-cycle progression, but not apoptosis induction. Moreover, downregulation of ZBTB24 increases the expression of IRF-4 (interferon regulatory factor 4) and Blimp-1 (B lymphocyte-induced maturation protein 1), two crucial factors involved in the proliferation and differentiation of B cells. Importantly, ZBTB24 exerts these functions independent of BCL-6 as it does not affect the expression and function of BCL-6. Our study thus not only provides a molecular explanation for the B-cell and antibody defects observed in ZBTB24-deficient ICF2 patients, but also indicates that ZBTB24 represents a novel transcriptional factor essentially involved in human B-cell functions.

Lack of association of single nucleotide polymorphisms of the bovine Flt-1 gene with growth traits in Chinese cattle breeds.

We analyzed 20 exons, with their intron-exon boundaries, of the bovine Flt-1 gene, using a strategy combining PCR amplification and single-strand conformational polymorphism analysis (PCR-SSCP), followed by nucleotide sequence analysis, in 675 cattle. We then looked for associations between polymorphisms and growth traits. Twelve novel SNPs (ss#184956516, ss#184956517, ss#184956518, ss#184956519, ss#251343993, ss#251343994, ss#251343995, ss#251343996, ss#251343997, ss#251343998, ss#251343999, and ss#251344000) were detected in the bovine Flt-1 gene in all three breeds. We observed no significant associations between these polymorphisms and birth weight, body weight and average daily gain during different growth periods (6, 12, 18, and 24 months old) (P > 0.05), or in body height, body length, heart girth, or height at the hip in Nanyang cattle breeds.

Myocardial oxidative stress contributes to transgenic ß2-adrenoceptor activation-induced cardiomyopathy and heart failure.

BACKGROUND AND PURPOSE: While maintaining cardiac performance, chronic ß-adrenoceptor activation eventually exacerbates the progression of cardiac remodelling and failure. We examined the adverse signalling pathways mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS) after chronic ß2-adrenoceptor activation. EXPERIMENTAL APPROACH: Mice with transgenic ß2-adrenoceptor overexpression (ß2-TG) and non-transgenic littermates were either untreated or treated with an antioxidant (N-acetylcysteine, NAC) or NADPH oxidase inhibitors (apocynin, diphenyliodonium). Levels of ROS, phosphorylated p38 mitogen-activated protein kinase (MAPK), pro-inflammatory cytokines and collagen content in the left ventricle (LV) and LV function were measured and compared. KEY RESULTS: ß2-TG mice showed increased ROS production, phosphorylation of p38 MAPK and heat shock protein 27 (HSP27), expression of pro-inflammatory cytokines and collagen, and progressive ventricular dysfunction. ß2-adrenoceptor stimulation similarly increased ROS production and phosphorylation of p38 MAPK and HSP27 in cultured cardiomyocytes. Treatment with apocynin, diphenyliodonium or NAC reduced phosphorylation of p38 MAPK and HSP27 in both cultured cardiomyocytes and the LV of ß2-TG mice. NAC treatment (500 mg·kg⁻¹ ·day⁻¹) for 2 weeks eliminated the up-regulated expression of pro-inflammatory cytokines and collagen in the LV of ß2-TG mice. Chronic NAC treatment to ß2-TG mice from 7 to 10 months of age largely prevented progression of ventricular dilatation, preserved contractile function (fractional shortening 37 ± 5% vs. 25 ± 3%, ejection fraction 52 ± 5% vs. 32 ± 4%, both P < 0.05), reduced cardiac fibrosis and suppressed matrix metalloproteinase activity. CONCLUSION AND IMPLICATIONS: ß2-adrenoceptor stimulation provoked NADPH oxidase-derived ROS production in the heart. Elevated ROS activated p38 MAPK and contributed significantly to cardiac inflammation, remodelling and failure.

Phytoestrogens from Psoralea corylifolia reveal estrogen receptor-subtype selectivity.

The seed of Psoralea corylifolia L. (PCL), a well-known traditional Chinese medicine, has been applied as a tonic or an aphrodisiac agent and commonly used as a remedy for bone fracture, osteomalacia and osteoporosis in China. In our study, the estrogen receptor subtype-selective activities of the extracts and compounds derived from PCL were analyzed using the HeLa cell assay. The different fractions including petroleum ether, CH(2)Cl(2) and EtOAc fractions of the EtOH extract of PCL showed significant activity in activating either ERalpha or ERbeta whereas the n-BuOH fraction showed no estrogenic activity. Further chromatographic purification of the active fractions yielded seven compounds including the two coumarins isopsoralen and psoralen, the four flavonoids isobavachalcone, bavachin, corylifol A and neobavaisoflavone, and the meroterpene phenol, bakuchiol. In reporter gene assay, the two coumarins (10(-8)-10(-5)M) acted as ERalpha-selective agonists while the other compounds (10(-9)-10(-6)M) activated both ERalpha and ERbeta. The estrogenic activities of all compounds could be completely suppressed by the pure estrogen antagonist, ICI 182,780, suggesting that the compounds exert their activities through ER. Only psoralen and isopsoralen as ERalpha agonists promoted MCF-7 cell proliferation significantly. Although all the compounds have estrogenic activity, they may exert different biological effects. In conclusion, both ER subtype-selective and nonselective activities in compounds derived from PCL suggested that PCL could be a new source for selective estrogen-receptor modulators.

Elevated levels of serum antibodies against Saccharomyces cerevisiae mannan in patients with systemic lupus erythematosus.

This study was undertaken to investigate whether levels of anti-Saccharomyces cerevisiae mannan antibodies (ASCMAs), a serological marker for Crohn's disease, seronegative spondyloarthritis and Behcet's disease, also correlate with systemic lupus erythematosus (SLE) in humans. Serum samples from healthy volunteers (n = 152) and patients with SLE (n = 40) were compared for ASCMA-IgA, -IgG and -IgM levels using enzyme linked immunosorbent assays. ASCMA-IgG, but not IgM and IgA, prevalence was significantly raised in active SLE patients (57.5%) compared with healthy controls (8.5%). ASCMA-IgG levels in SLE patients during remission were relatively lower, indicating a possible correlation with disease activity. These results differ from a previous study, which did not detect a difference between ASCMA levels in SLE patients and healthy control. It remains to be evaluated whether elevated ASCMA-levels are common to all rheumatic disorders.

Elevated expression of transmembrane IL-15 in immune cells correlates with the development of murine lupus: a potential target for immunotherapy against SLE.

Presentation in trans by the Interleukin-15 receptor alpha chain (IL-15Ralpha) has been suggested as the main mechanism for IL-15 anchoring to the cell surface, but it is also evident that IL-15 can exist as a transmembrane protein. We herein demonstrate that replacement of the first 41 residues of human IL-15 (hIL-15) with Igkappa chain leader sequence resulted in secretion of most of the recombinant hIL-15 expressed in transfectant cells, thus identifying the transmembrane region of IL-15. A fusion protein (hIL-15Ralpha-Fc) between the extracellular domain of hIL-15Ralpha and the Fc fragment of IgG1 was prepared and shown to be able to bind with transmembrane IL-15 (tmIL-15). The level of tmIL-15 expression in macrophages, activated T cells and B cells from 6-month-old BXSB male mice, an animal model for systemic lupus erythematosus (SLE), was significantly increased compared with that from BXSB females or young males. In addition, hIL-15Ralpha-Fc was able to block the T cell stimulating and anti-apoptotic effect of the tmIL-15-positive BXSB macrophages in vitro. Intravenous administration of hIL-15Ralpha-Fc reduced the titre of autoantibodies against dsDNA and also proteinuria in aged BXSB males, implying that neutralization of IL-15 activity in vivo may be an effective way of treating SLE.

Knockout of beta(1)- and beta(2)-adrenoceptors attenuates pressure overload-induced cardiac hypertrophy and fibrosis.

BACKGROUND AND PURPOSE: The role of beta-adrenoceptors in heart disease remains controversial. Although beta-blockers ameliorate the progression of heart disease, the mechanism remains undefined. We investigated the effect of beta-adrenoceptors on cardiac hypertrophic growth using beta(1)- and beta(2)-adrenoreceptor knockout and wild-type (WT) mice. EXPERIMENTAL APPROACH: Mice were subjected to aortic banding or sham surgery, and their cardiac function was determined by echocardiography and micromanometry. KEY RESULTS: At 4 and 12 weeks after aortic banding, the left ventricle:body mass ratio was increased by 80-87% in wild-type mice, but only by 15% in knockouts, relative to sham-operated groups. Despite the blunted hypertrophic growth, ventricular function in knockouts was maintained. WT mice responded to pressure overload with up-regulation of gene expression of inflammatory cytokines and fibrogenic growth factors, and with severe cardiac fibrosis. All these effects were absent in the knockout animals. CONCLUSION AND IMPLICATIONS: Our findings of a markedly attenuated cardiac hypertrophy and fibrosis following pressure overload in this knockout model emphasize that beta-adrenoceptor signalling plays a central role in cardiac hypertrophy and maladaptation following pressure overload.

Preserved ventricular contractility in infarcted mouse heart overexpressing beta(2)-adrenergic receptors.

Effects of cardiac specific overexpression of beta(2)-adrenergic receptors (beta(2)-AR) on the development of heart failure (HF) were studied in wild-type (WT) and transgenic (TG) mice following myocardial infarction (MI) by coronary artery occlusion. Animals were studied by echocardiography at weeks 7 to 8 and by catheterization at week 9 after surgery. Post-infarct mortality, due to HF or cardiac rupture, was not different among WT mice, and there was no difference in infarct size (IS). Compared with the sham-operated group (all P < 0.01), WT mice with moderate (<36%) and large (>36%) IS developed lung congestion, cardiac hypertrophy, left ventricular (LV) dilatation, elevated LV end-diastolic pressure (LVEDP), and suppressed maximal rate of increase of LV pressure (LV dP/dt(max)) and fractional shortening (FS). Whereas changes in organ weights and echo parameters were similar to those in infarcted WT groups, TG mice had significantly higher levels of LV contractility in both moderate (dP/dt(max) 4,862 +/- 133 vs. 3,694 +/- 191 mmHg/s) and large IS groups (dP/dt(max) 4,556 +/- 252 vs. 3,145 +/- 312 mmHg/s, both P < 0.01). Incidence of pleural effusion (36% vs. 85%, P < 0.05) and LVEDP levels (6 +/- 0.3 vs. 9 +/- 0.8 mmHg, P < 0.05) were also lower in TG than in WT mice with large IS. Thus beta(2)-AR overexpression preserved LV contractility following MI without adverse consequence.

Serial echocardiographic assessment of left ventricular dimensions and function after myocardial infarction in mice.

OBJECTIVE: To test the usage of serial echocardiography in mice with induced myocardial infarct (MI) and to characterize the mouse model of MI. METHODS: C57 mice underwent open-chest surgery to induce left coronary artery occlusion or sham-operation (SH). Echocardiography was performed before and at 1, 2.5, 6 and 9 weeks after surgery. Left ventricular end diastolic and end systolic dimensions (LVEDd, LVESd) and fractional shortening (FS) were measured. Haemodynamics was determined at week 9 by LV catheterization and hearts were examined morphologically. RESULTS: Post-infarct mortality was 46% (10/22), of which, 70% died of acute heart failure or LV rupture within the first week. LV dimensions and FS remained stable in SH group (n = 10) during the study period. In surviving MI mice (n = 12), there was modest LV dilatation and fall in FS at week 1. Compared with week 0 values, there were progressive increase in LVEDd (+50(-)+66%) and LVESd (+124(-)+171%), and decline in FS (-53(-)-73%) during the 2.5-9 week period. Infarcted mice also had lower LV systolic pressure (LVSP), dP/dtmax and dP/dtmin (all P < 0.01 vs. SH group). Infarct size, LVSP and dP/dt significantly correlated with FS and LV dimensions (r = 0.61-0.80, all P < 0.01). CONCLUSIONS: LV remodeling and dysfunction in mice with MI are time-dependent processes and early remodeling seems associated with high risk of rupture and acute pump failure. Our findings provide a baseline description of this murine model and confirm echocardiography as a reliable means to serially assess changes of cardiac structure and function after MI.

Characterisation of Candida albicans infections of haematogenous and mucosal origin in mice lacking the interferon gamma receptor protein.

Mice harbouring a null deletion mutation in the IFNgamma receptor gene were used to study the role of IFNgamma responsiveness during experimental systemic candidiasis of mucosal or haematogenous origin. After intravenous (i.v.) or intranasal (i.n.) challenge with Candida albicans the progression of infection and concomitant cellular and antibody anti-C. albicans immune responses were analysed. During the week following i.v. challenge, the rate of C. albicans multiplication in kidneys, liver and spleen was faster in IFNgammaR (-/-) than IFNgammaR (+/+) mice. As a result, IFNgammaR (-/-) mice perished earlier than IFNgammaR (+/+) mice when challenged with equal numbers of live yeast cells. However, the overall susceptibility of the two mouse strains, in terms of survival against different C. albicans challenge doses over a 60-day period, was similar. No differences were found in the cellular anti-C. albicans response generated by i.v. challenge in both mouse strains. In contrast the kinetics and strength of the serum anti-C. albicans antibody responses were markedly different. Significantly stronger, predominantly IgG2a antibody responses accompanied the eventual control of C. albicans infection in IFNgammaR (-/-) mice. Following intranasal challenge, there was no difference in the rate of C. albicans clearance from the lungs of IFNgammaR (-/-) and IFNgammaR (+/+) mice. However, 48 h after challenge, large, conspicuous abscesses appeared in the lungs, liver, kidneys and spleen of IFNgammaR (-/-) mice. These abscesses were characterised by the presence of C. albicans and abundant neutrophilic infiltrates, but very few macrophages. No such abscesses developed in i.n. challenged IFNgammaR (+/+) mice. In both mouse strains, i.n. challenge induced strong systemic anti-C. albicans cellular responses, but relatively low titre systemic antibody responses. Mucosal anti-C. albicans antibody responses were detected in IFNgammaR (+/+), but not IFNgammaR (-/-) mice. Splenic adherent macrophages obtained from IFNgammaR (-/-) mice exhibited a significantly lower candidacidal activity than those of IFNgammaR (+/+) mice, and as expected, were not responsive to IFNgamma. In summary, these data suggest that IFNgamma has a role in limiting C. albicans multiplication during the early stages of infection, as well as in preventing the development of C. albicans-associated abscesses. Activation of macrophages by IFNgamma might be pivotal in mediating this role.