Feature tracking for assessment of diastolic function by cardiovascular magnetic resonance imaging.

AIM: To assess the agreement of cardiovascular magnetic resonance imaging (CMRI) feature-tracking (FT) parameters with echocardiography to diagnose diastolic dysfunction; to determine whether a similar parameter to mitral inflow early diastolic velocity to early diastolic tissue velocity ratio (E/e') can increase accuracy of imaging by dividing the phase contrast (PC) mitral inflow E-wave (E) with a CMRI-FT parameter; to compare the agreement between CMRI-FT and PC diastolic function assessment using echocardiography. MATERIALS AND METHODS: Patients (n=71; 43 abnormal diastolic function) undergoing both CMRI and echocardiography independently were included. Echocardiography was the reference standard. CMRI-FT analysed the short and long axis cine contours. PC images of mitral inflow, tissue velocity, pulmonary vein flow, and left atrial area were assessed. RESULTS: Using CMRI-FT, the area under the curve (AUC) for identifying diastolic dysfunction was >0.80 for radial and circumferential strain, systolic strain rate (SSR), and early diastolic strain rate (DSR). For cases with CMRI-determined left ventricular ejection fraction (LVEF) ≥50% (n=38), circumferential DSR was the only parameter with good accuracy (AUC=0.87; cut-off 0.93/s). E/circumferential DSR ratio and longitudinal strain had high accuracy in all patients (AUC=0.88 and 0.93 respectively) and CMRI-determined LVEF ≥50% (AUC=0.81; cut-off 76.7). Circumferential DSR showed the highest agreement with echocardiography (higher than E/circumferential DSR and PC assessment) in all cases (kappa 0.75; p<0001) and cases with CMRI LVEF ≥50% (kappa 0.73; p<0.0001). CONCLUSIONS: CMRI-FT circumferential DSR showed the highest accuracy for determining diastolic dysfunction with good agreement with echocardiography. Circumferential DSR had higher accuracy than E/circumferential DSR and PC.

[Jinghuaweikang capsules combined with Quadruple therapy in the treatment of Helicobacter pylori infection:a multicenter,randomized,controlled,clinical study].

Objective: To explore the efficacy of Jinghuaweikang capsules combined with Quadruple therapy in the treatment of Helicobacter pylori (H.pylori)infection. Methods: Patients who were infected with H.pylori in 7 centers in Gansu Province were recruited in this prospective simple randomized study. All the patients are divided into four groups randomly: patients in Group A1 were treated with esomeprazole (20 mg, twice a day) + pectin bismuth (200 mg, three times a day) + amoxicillin (1 000 mg, twice a day) + clarithromycin (500 mg, twice a day), while Group A2 with Jinghuaweikang capsules(160 mg, three times a day) based on group A2, Group B1 with esomeprazole (20 mg, twice a day) + bismuth pectin (200 mg, three times a day) + amoxicillin (1 000 mg, twice a day) + furazolidone (100 mg, twice a day) and Group B2 with Jinghuaweikang capsules(160 mg, three times a day) based on group B2. The treatment time was 14 days for all 4 groups. In the course of treatment, abdominal pain, acid reflux, abdominal distension, belching, hiccups were observed at the time before treatment, 14 days and 30 days after treatment and were scored. Finally, all patients received (13)C or (14)C for H.pylori at the time of 30 days after the treatment. Result: A total of 455 patients were included in 7 hospitals from February 2016 to May 2017 in Gansu province, and there were 189 male patients. Group A1 included 129 cases, group A2 96 cases, group B1 112 cases and group B2 118 cases. The eradication rates that accorded with program data analysis (PP) were A1[46.9%(60/128)], A2[63.8%(60/94)], B1[60.7%(68/112)], B2[68.6%(81/118)] (P<0.004). Compared with group A1, the eradication rate of H.pylori in group B1 and group A2 increased (P<0.001, P=0.032), there was no statistical difference between group B2 and group A2, group B1 and group B2 (P=0.208, P=0.461). According to intentional analysis (ITT), the eradication rates of H.pylori in group A1 were 46.5% (60/129),group A2 were 62.5% (60/96),group B1 were 60.7% (68/112),and group B2 were 68.6% (81/118).The radical rate of A2 was higher than A1 (P=0.017), group B2 was not higher than group B1 (P=0.208), and there was no significant difference among the other groups. The symptoms of abdominal pain, abdominal distention, acid reflux, belching and hiccup in the group A2 and group B2 were improved than those in group A1 and group B1 (P<0.05). No serious adverse reactions occurred in all groups. Conclusion: Jinghuaweikang capsules can improve the eradication rate of Helicobacter pylori, and improve the symptoms of patients.

The clinical value of hepatic extracellular volume fraction using routine multiphasic contrast-enhanced liver CT for staging liver fibrosis.

AIM: To investigate the value of hepatic extracellular volume fractions (fECVs) measured using routine liver computed tomography (CT) evaluating liver fibrosis (LF). MATERIALS AND METHODS: A total of 60 patients (male:female ratio, 39:21; mean age, 42.4 years) histologically diagnosed with LF underwent routine liver CT. Absolute enhancement (in Hounsfield units) of the liver parenchyma (Eliver) and aorta (Eaorta) 3 minutes after contrast medium administration was calculated using precontrast and equilibrium phase scans. The fECV was calculated using the following equation: fECV (%)=Eliver× (100 - haematocrit [%])/Eaorta. Correlation between fECV and LF stage was evaluated using the Spearman correlation coefficient. The fECVs were compared between each stage of LF. The diagnostic performance of fECV was assessed using receiver operating characteristic (ROC) curve analysis. RESULTS: The difference among the groups was statistically significant (p<0.05). The fECVs were significantly different (p<0.05) between F0 versus F4, F1 versus F4, and F2 versus F4. The fECVs showed a significant correlation with pathological LF staging (r=0.468, p=0.001). The sensitivity and specificity were 0.76 and 0.68 for severe LF (F≥3); and 0.89 and 0.63 for cirrhosis (F=4). The areas under the ROC curve (AUCs) for F≥3 and F=4 were 0.757 and 0.775, respectively. CONCLUSIONS: Calculation of fECV during routine contrast-enhanced liver CT may provide a non-invasive means of assessing LF.

Network meta-analysis of Chinese herb injections combined with FOLFOX chemotherapy in the treatment of advanced colorectal cancer.

WHAT IS KNOWN AND OBJECTIVE: Research has indicated that some Chinese herb injections (CHIs) might be beneficial in combination with chemotherapy, including remedies that might be used as effective chemosensitizers and radiosensitizers, or as palliative therapy. Here, we carried out a network meta-analysis to assess the clinical efficacy and safety of CHIs combined with oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX) for advanced colorectal cancer (CRC). METHODS: PubMed, EMBASE.com, the Cochrane Central Register of Controlled Trials (CENTRAL), Chinese Biomedical Literature Database (CBM), Wanfang Database and Chinese Journal Full-text Database were searched from inception to 31 December 2014, to identify relevant randomized controlled trails (RCTs). The risk of bias in included RCTs was evaluated according to the Cochrane Handbook version 5.1.0. Standard pairwise meta-analysis and Bayesian network meta-analysis were performed to compare the efficacy and safety of different CHIs combined with FOLFOX. Data were analysed using STATA 12.0 and WinBUGS1.4 software. RESULTS AND DISCUSSION: We identified 63 eligible studies (with 4837 patients in total), involving 9 CHIs. Pairwise meta-analysis showed that compared with FOLFOX alone, combinations with Aidi injection and compound matrine injection could significantly improve the overall response rate and quality of life and reduce the incidence of nausea and vomiting (III-IV), diarrhoea (III-IV), thrombocytopenia (III-IV), leukopenia (III-IV) and peripheral neurotoxicity (III-IV). According to results of indirect comparison, there were no statistically significant differences for most of comparison groups. Aidi+FOLFOX, shenqifuzheng+FOLFOX and compound matrine+FOLFOX had the greatest probability of being the best treatment in clinical efficacy and safety, considering the small sample size. WHAT IS NEW AND CONCLUSIONS: Most of the included studies were of low quality, and there was a scarcity of eligible trials and numbers of participants. Based on currently limited evidence, aidi, shenqifuzheng and compound matrine were superior to other CHIs in patients receiving FOLFOX chemotherapy for advanced CRC. More studies are required to confirm the efficacy of CHIs in combination with FOLFOX for advanced CRC.

Landau renormalizations of superfluid density in the heavy-fermion superconductor CeCoIn5.

The formation of heavy-fermion bands can occur by means of the conversion of a periodic array of local moments into itinerant electrons via the Kondo effect and the huge consequent Fermi-liquid renormalizations. Leggett predicted for liquid (3)He that Fermi-liquid renormalizations change in the superconducting state, leading to a temperature dependence of the London penetration depth Λ quite different from that in BCS theory. Using Leggett's theory, as modified for heavy fermions, it is possible to extract from the measured temperature dependence of Λ in high quality samples both Landau parameters F(0)(s) and F(1)(s); this has never been accomplished before. A modification of the temperature dependence of the electronic specific heat C(el), related to that of Λ, is also expected. We have carefully determined the magnitude and temperature dependence of Λ in CeCoIn(5) by muon spin relaxation rate measurements to obtain F(0)(s) = 36 ± 1 and F(1)(s) = 1.2 ± 0.3, and we find a consistent change in the temperature dependence of C(el). This, the first determination of F(1)(s) with a value ≪ F(0)(s) in a heavy-fermion compound, tests the basic assumption of the theory of heavy fermions, that the frequency dependence of the self-energy is much more important than its momentum dependence.

Measurement of an enhanced superconducting phase and a pronounced anisotropy of the energy gap of a strained FeSe single layer in FeSe/Nb:SrTiO3/KTaO3 heterostructures using photoemission spectroscopy.

Single-layer FeSe films with an extremely expanded in-plane lattice constant of 3.99±0.02 Å are fabricated by epitaxially growing FeSe/Nb:SrTiO3/KTaO3 heterostructures and studied by in situ angle-resolved photoemission spectroscopy. Two elliptical electron pockets at the Brillouin zone corner are resolved with negligible hybridization between them, indicating that the symmetry of the low-energy electronic structure remains intact as a freestanding single-layer FeSe, although it is on a substrate. The superconducting gap closes at a record high temperature of 70 K for the iron-based superconductors. Intriguingly, the superconducting gap distribution is anisotropic but nodeless around the electron pockets, with minima at the crossings of the two pockets. Our results place strong constraints on current theories.

Efficacy of immunotherapy-based immediate cytoreductive nephrectomy vs. deferred cytoreductive nephrectomy in metastatic renal cell carcinoma.

OBJECTIVE: This study was performed to evaluate the efficacy of immediate cytoreductive nephrectomy (CRN) followed by programmed cell death factor-1 (PD-1) inhibitors vs. deferred CRN after the administration of 4 cycles of neoadjuvant therapy using nivolumab preceding the debulking and postoperative chemotherapy in metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: We recruited 84 patients with primary mRCC admitted to our Oncology Department from 2018 to 2020 and randomized them 1:1 to receive either CRN followed by nivolumab (control group) or 4 cycles of neoadjuvant therapy using nivolumab before CRN and postoperative chemotherapy (study group), with 42 patients in each group. The primary clinical endpoints were the clinical efficacy and safety of the PD-1 antibody. Clinical outcomes were assessed 3 months after treatment. RESULTS: Patients were followed-up for 10-52 months, with a median follow-up period of 40.50 months. The control group reported 2 cases of complete remission and 10 cases of partial remission, with an objective response rate (ORR) of 28.57% (12/42). The study group reported 4 cases of complete remission and 14 cases of partial remission with an ORR of 42.86% (18/42). No significant differences in the ORR were identified between the two groups (p > 0.05). Progression-free survival of the patients was significantly extended from 30 months (19-51) to 43 months (38-76) after administrating the PD-1 inhibitors before the debulking (HR = 0.501, 95% CI: 0.266 to 0.942). There were no significant differences in the median survival of patients between the two groups [44 months (38-79) vs. 44 months (32-81)] (HR = 0.814, 95% CI: 0.412 to 1.612). The two protocols had a similar safety profile. CONCLUSIONS: Nivolumab administration preceding delayed CRN provides significant progression-free survival benefits for patients with mRCC, but its impact on overall survival requires further investigations.

[Evaluation of the impact of the Japanese encephalitis vaccine included in an expanded immunization program on the reported incidence rate of Japanese encephalitis in Gansu province-based on interrupted time series].

Objective: To evaluate the impact of the Japanese encephalitis vaccine included in an expanded immunization program on the reported incidence rate of Japanese encephalitis in Gansu province. Methods: Information on the reported incidence rate of Japanese encephalitis in Gansu province from 1987 to 2019 was collected through the National Population Health Science Data Center and the China Disease Prevention and Control Information System. In addition, the trend of Japanese encephalitis reported incidence rate in Gansu province before and after the inclusion of the Japanese encephalitis vaccine in the expanded immunization program was analyzed using an interrupted time-series design. Results: The annual reported incidence rate of Japanese encephalitis in Gansu province from 1987 to 2019 was 0.448/per 100 000. However, after the inclusion of the Japanese encephalitis vaccine in the expanded immunization program in Gansu province in 2008, the amount of change in the level of Japanese encephalitis reported incidence rate was -2.223/per 100 000 (t=-2.90, P=0.007), the amount of change in the slope of Japanese encephalitis reported incidence rate was 0.082 (t=2.87, P=0.008) with the slope of Japanese encephalitis reported incidence rate as 0.071 (ß1+ß3=0.071). Conclusions: The Japanese encephalitis vaccine has achieved good prevention and control effects in Gansu province in the short term after its inclusion in the expanded immunization program, but outbreaks of Japanese encephalitis have still occurred. Therefore, in the future, Gansu province should promptly adjust the immunization strategy of the Japanese encephalitis vaccine, and strengthen the vaccination of the adult population, especially the rural adult population in the southeastern region of Gansu province, based on the continued focus on the works on Japanese encephalitis vaccination for children and adolescents.

Low expression of microRNA-1266 promotes colorectal cancer progression via targeting FTO.

OBJECTIVE: To explore the role of microRNA-1266 in colorectal cancer (CRC) and its underlying mechanism. PATIENTS AND METHODS: The expression level of microRNA-1266 in 48 CRC tissues and paracancerous tissues was detected by quantitative Real-time-polymerase chain reaction (qRT-PCR). The relationship between microRNA-1266 expression and basic characteristics of CRC patients was analyzed. The effect of microRNA-1266 on the viability of CRC cells was detected by cell counting kit-8 (CCK-8) assay. Subsequently, a potential target gene for microRNA-1266 was predicted through bioinformatics. Finally, the binding condition between microRNA-1266 and the target gene was verified by RNA binding protein immunoprecipitation (RIP) and luciferase reporter gene assay, respectively. RESULTS: MicroRNA-1266 was lowly expressed in 48 cases of CRC tissues than that of paracancerous tissues. Clinical data demonstrated that microRNA-1266 expression was correlated to tumor size and TNM of CRC patients. Knockdown of microRNA-1266 promoted proliferation of CRC cells. FTO was predicted to be the target gene for microRNA-1266, which was negatively regulated by microRNA-1266. CONCLUSIONS: MicroRNA-1266 is lowly expressed in CRC tissues than that of paracancerous tissues. Lowly expressed microRNA-1266 promotes the occurrence and progression of CRC by directly targeting FTO.

[Association between fatty liver and type 2 diabetes in the baseline population of Jinchang Cohort].

Objective: To explore the association between fatty liver and type 2 diabetes mellitus (T2DM) in the baseline-population of Jinchang cohort study. Methods: Data from all the participants involved in the baseline-population of Jinchang cohort study was used, to compare the risks of T2DM in fatty liver and non fatty liver groups and to explore the interaction between family history or fatty liver of diabetes and the prevalence of T2DM. Results: Among all the 46 861 participants, 10 574 were diagnosed as having fatty liver (22.56%), with the standardized rate as 20.66%. Another 3 818 participants were diagnosed as having T2DM (8.15%) with standardized rate as 6.90%. The prevalence of T2DM increased in parallel with the increase of age (trend χ(2)=2 833.671, trend P<0.001). The prevalence of T2DM in the fatty liver group was significantly higher than that in the non-fatty liver group, both in men or women and in the overall population. Compared with the group of non-fatty liver, the risks of T2DM in fatty liver group were seen 1.78 times higher in males, 2.33 times in women and 2.10 times in the overall population, after adjustment for factors as age, levels of education, smoking, drinking, physical exercise, BMI, family history of diabetes and some metabolic indicators (pressure, TC, TG, uric acid, ALT, AST, gamma-glutamyl transferase). Date from the interaction model showed that fatty liver and family history of diabetes present a positive additive interaction on T2DM (RERI=1.18, 95%CI: 0.59-1.78; AP=0.24, 95%CI: 0.14-0.34; S=1.43, 95%CI: 1.21-1.69). Conclusions: Fatty liver could significantly increase the risk of T2DM and a positive additive interaction was also observed between fatty liver and family history of diabetes on T2DM. It was important to strengthen the prevention program on T2DM, in order to effectively control the development of fatty liver.

[Effect of combination model on fitting cancer mortality and prediction].

Objective: To reduce the cancer burden in the Jinchang cohort and provide evidence for developing cancer prevention strategies and performing effectiveness evaluation in the Jinchang cohort. We are fitting thirteen years of cancer mortality data from the Jinchang cohort by using six kinds of predicting methods to compare relative fitness and to select good predicting methods for the prediction of cancer mortality trends. Methods: The mortality data of cancer in Jinchnag cohort from 2001-2013 were fitted using six kinds of predicting methods: dynamic series, linear regression, exponential smoothing, autoregressive integrated moving average (ARIMA) model, grey model (GM), and Joinpoint regression. Weight coefficients of combination models were calculated by four methods: the arithmetic average method, the variance inverse method, the mean square error inverse method, and the simple weighted average method. Results: The cancer mortality was fitted and compared by using six kinds of forecasting methods; the fitting precision of the Joinpoint linear regression had the highest accuracy (87.64%), followed by linear regression (87.32%), the dynamic series (86.99%), GM (1, 1) (86.25%), exponential smoothing (85.72%) and ARIMA (1, 0, 0) (81.98%), respectively. Prediction accuracy of the combination model derived from GM (1, 1) and linear regression (>99%) was higher than that of the combination model derived from ARIMA (1, 0, 0) and GM (1, 1). The combination model derived from the GM (1, 1) and linear regression, with weight coefficients based on the arithmetic average method and the mean square error inverse method, had the best prediction effect of the four weight calculation methods. Conclusion: Prediction accuracy of the combination model, with accuracy >95%, was higher than that of the single prediction methods.

[Evaluation of estimation of prevalence ratio using bayesian log-binomial regression model].

To evaluate the estimation of prevalence ratio (PR) by using bayesian log-binomial regression model and its application, we estimated the PR of medical care-seeking prevalence to caregivers' recognition of risk signs of diarrhea in their infants by using bayesian log-binomial regression model in Openbugs software. The results showed that caregivers' recognition of infant' s risk signs of diarrhea was associated significantly with a 13% increase of medical care-seeking. Meanwhile, we compared the differences in PR's point estimation and its interval estimation of medical care-seeking prevalence to caregivers' recognition of risk signs of diarrhea and convergence of three models (model 1: not adjusting for the covariates; model 2: adjusting for duration of caregivers' education, model 3: adjusting for distance between village and township and child month-age based on model 2) between bayesian log-binomial regression model and conventional log-binomial regression model. The results showed that all three bayesian log-binomial regression models were convergence and the estimated PRs were 1.130(95%CI: 1.005-1.265), 1.128(95%CI: 1.001-1.264) and 1.132(95%CI: 1.004-1.267), respectively. Conventional log-binomial regression model 1 and model 2 were convergence and their PRs were 1.130(95% CI: 1.055-1.206) and 1.126(95% CI: 1.051-1.203), respectively, but the model 3 was misconvergence, so COPY method was used to estimate PR, which was 1.125 (95%CI: 1.051-1.200). In addition, the point estimation and interval estimation of PRs from three bayesian log-binomial regression models differed slightly from those of PRs from conventional log-binomial regression model, but they had a good consistency in estimating PR. Therefore, bayesian log-binomial regression model can effectively estimate PR with less misconvergence and have more advantages in application compared with conventional log-binomial regression model.

[Study on the classification of dominant pathogens related to febrile respiratory syndrome, based on the method of Bayes discriminant analysis].

Objective: To understand the dominant pathogens of febrile respiratory syndrome (FRS) patients in Gansu province and to establish the Bayes discriminant function in order to identify the patients infected with the dominant pathogens. Methods: FRS patients were collected in various sentinel hospitals of Gansu province from 2009 to 2015 and the dominant pathogens were determined by describing the composition of pathogenic profile. Significant clinical variables were selected by stepwise discriminant analysis to establish the Bayes discriminant function. Results: In the detection of pathogens for FRS, both influenza virus and rhinovirus showed higher positive rates than those caused by other viruses (13.79%, 8.63%), that accounting for 54.38%, 13.73% of total viral positive patients. Most frequently detected bacteria would include Streptococcus pneumoniae, and haemophilus influenza (44.41%, 18.07%) that accounting for 66.21% and 24.55% among the bacterial positive patients. The original-validated rate of discriminant function, established by 11 clinical variables, was 73.1%, with the cross-validated rate as 70.6%. Conclusion: Influenza virus, Rhinovirus, Streptococcus pneumoniae and Haemophilus influenzae were the dominant pathogens of FRS in Gansu province. Results from the Bayes discriminant analysis showed both higher accuracy in the classification of dominant pathogens, and applicative value for FRS.

Tuning the band structure and superconductivity in single-layer FeSe by interface engineering.

The interface between transition metal compounds provides a rich playground for emergent phenomena. Recently, significantly enhanced superconductivity has been reported for single-layer FeSe on Nb-doped SrTiO3 substrate. Yet it remains mysterious how the interface affects the superconductivity. Here we use in situ angle-resolved photoemission spectroscopy to investigate various FeSe-based heterostructures grown by molecular beam epitaxy, and uncover that electronic correlations and superconducting gap-closing temperature (Tg) are tuned by interfacial effects. Tg up to 75 K is observed in extremely tensile-strained single-layer FeSe on Nb-doped BaTiO3, which sets a record high pairing temperature for both Fe-based superconductor and monolayer-thick films, providing a promising prospect on realizing more cost-effective superconducting device. Moreover, our results exclude the direct correlation between superconductivity and tensile strain or the energy of an interfacial phonon mode, and highlight the critical and non-trivial role of FeSe/oxide interface on the high Tg, which provides new clues for understanding its origin.

Electronic structure of Eu(Fe0.79Ru0.21)2As2 studied by angle-resolved photoemission spectroscopy.

Eu(Fe(0.79)Ru(0.21))2As2 is suggested to be a nodeless superconductor based on the empirical correlation between pnictogen height (hPn) and superconducting gap behavior, in contrast to BaFe2(As(0.7)P(0.3))2 and Ba(Fe(0.65)Ru(0.35))2As2. We studied the low-lying electronic structure of Eu(Fe(0.79)Ru(0.21))2As2 with angle-resolved photoemission spectroscopy (ARPES). By photon energy dependence and polarization dependence measurements, we resolved the band structure in the three-dimensional momentum space and determined the orbital character of each band. In particular, we found that the dz2 -originated ζ band does not contribute spectral weight to the Fermi surface around Z, unlike BaFe2(As(0.7)P(0.3))2 and Ba(Fe(0.65)Ru(0.35))2As2. Since BaFe2(As(0.7)P(0.3))2 and Ba(Fe(0.65)Ru(0.35))2As2 are nodal superconductors and their hPn's are less than 1.33 Å, while the hPn of Eu(Fe(0.79)Ru(0.21))2As2 is larger than 1.33 Å, our results provide more evidence for a direct relationship between nodes, dz2 orbital character and hPn. Our results help to provide an understanding of the nodal superconductivity in iron-based superconductors.

Immune complexes bind preferentially to specific subpopulations of human erythrocytes.

Primate erythrocytes have complement receptors (CR1) that, both in vivo and in vitro, bind immune complexes (IC) opsonized with C3b. The present study was undertaken to determine whether the ability of human erythrocytes to bind IC is a characteristic shared by all erythrocytes. Binding of IC to erythrocytes probably involves the interaction of several C3b molecules with several CR1 clustered in small areas of the erythrocyte surface. To identify IC binding CR1 clusters, we first assessed the binding to erythrocytes of fluorescein-labeled polystyrene beads coated with monoclonal anti-CR1 antibodies (anti-CR1-beads) and second, performed IC. The binding of these ligands to erythrocytes was evaluated by immunofluorescence microscopy and flow cytometry. We found that only a fraction of erythrocytes from normal individuals bound anti-CR1-beads specifically and the percentage of erythrocytes able to bind beads increased with increasing numbers of CR1 per erythrocyte. However, the number of anti-CR1-beads bound per erythrocyte varied among cells from the same individual. We demonstrated further that the erythrocyte binding sites for anti-CR1-beads are also binding sites for opsonized IC. This was shown by demonstrating that anti-CR1-beads inhibited the binding of opsonized IC to erythrocytes and opsonized IC inhibited the binding of anti-CR1-beads to erythrocytes. Incubation of erythrocytes with opsonized IC, followed by FITC-labeled secondary antibodies, confirmed that indeed only a fraction of erythrocytes is capable of binding opsonized IC and that the binding sites for IC occupy small regions on the erythrocyte membrane. By contrast, we demonstrated that greater than 90% of erythrocytes express CR1. In conclusion, only some erythrocytes have the capacity to bind IC. Differences in the ability of erythrocytes to bind IC are probably related to differences in the clustering of CR1 in the erythrocyte membrane. Anti-CR1-beads identify erythrocyte binding sites for IC. These beads should prove useful to assess the changes that occur in the erythrocyte CR1 after exposure to IC in vivo.

The chimpanzee and cynomolgus monkey erythrocyte immune adherence receptors are encoded by CR1-like genes.

The human erythrocyte immune adherence (IA) receptor is the Mr 220,000 type one complement receptor, or CR1. Nonhuman primate IA receptors are comprised of a family of smaller erythrocyte complement receptors (E-CRs) of unknown origin. Recently, the Mr 65,000 baboon E-CR was identified as a glycophosphatidylinositol (GPI)-linked protein encoded by a partially duplicated CR1 gene termed CR1-like. The purpose of this study was to determine the genetic origin of the Mr 75,000 chimpanzee E-CR. Two previously identified cDNAs, an alternative splice product of CR1 termed CR1a and a chimpanzee form of CR1-like, were synthesized and amplified from chimpanzee bone marrow RNA, and transiently expressed in COS-7 cells. By SDS-PAGE, the CR1a protein had a relative mobility slightly greater than chimpanzee E-CR, whereas that of the CR1-like protein was slightly less. Affinity chromatography demonstrated that little chimpanzee CR1a bound to human C3i linked to activated thiol-Sepharose (C3i-ATS), while over 50% of both chimpanzee CR1-like and chimpanzee E-CR bound to C3i-ATS. Treatment with phosphatidylinositol-specific phospholipase C (PIPLC) to assess GPI linkage released E-CR from chimpanzee erythrocytes, and E-CR from cynomolgus monkey erythrocytes. Based on size, ligand-binding specificity, and PIPLC sensitivity, we conclude that the chimpanzee E-CR is encoded by the CR1-like gene. Furthermore, based on PIPLC sensitivity, the cynomolgus monkey E-CR is also likely encoded by a CR1-like sequence. Thus, CR1-like, which is a genetic element of unknown significance in humans, is the gene that encodes the erythrocyte IA receptor of many nonhuman primates.

Rate of antigen entry into the circulation in experimental versus naturally occurring immune complex glomerulonephritis.

This study tested the hypothesis that the rate of antigen entry into the circulation in systemic lupus erythematosus (SLE), a naturally occurring immune complex glomerulonephritis (IC-GN), is slow compared with that of traditional experimental models of IC-GN, in which the antigen is delivered rapidly as a daily iv bolus. This hypothesis was tested by comparing rates of decline of the third component of complement (C3) and of circulating neutrophils (PMN) in SLE patients with active disease with those of cynomolgus monkeys (CYN) undergoing induction of experimental IC-GN by means of a daily bolus infusion of antigen. It has previously been shown that, as antigen enters the circulation and forms circulating IC, C3 levels and circulating PMN decline acutely. Thus, acute changes in these parameters can be surrogates for the rate of antigen entry into the circulation. In the CYN undergoing induction of IC-GN (N = 11), infusion of the antigen (bovine gamma-globulin) over 10 min resulted in acute declines in C3 levels (25 +/- 6.6%; P = 0.0018 and PMN counts (59 +/- 9%; P < 0.0002). In addition, the CYN experienced the onset of acute respiratory distress and hypotension. By contrast, in patients with active SLE (N = 9), C3 and white blood cell counts measured at 24-h intervals did not change significantly, and episodes of acute hypotension or respiratory distress were not observed. In the CYN, the onset of visible vasculitic lesions in the omentum were also documented within minutes of the infusion of bovine gamma-globulin. The rapidity of onset of these vascular lesions suggests that the tempo at which lesions develop in experimental models of IC disease is faster than that of naturally occurring IC diseases. It was concluded that, in naturally occurring IC diseases, antigen probably enters the circulation slowly over prolonged periods of time, rather than as large boluses over short periods of time, as in traditional experimental models of IC-GN. Thus, models of IC-GN involving a daily bolus infusion of antigen may not be clinically relevant, particularly when IC clearing mechanisms are tested, because the efficiency of these mechanisms may be markedly influenced by the rate at which IC form in the circulation.

Primary sequence of an alternatively spliced form of CR1. Candidate for the 75,000 M(r) complement receptor expressed on chimpanzee erythrocytes.

Chimpanzee erythrocytes express a 75,000 M(r) complement receptor (E-CR) that binds C3b bearing immune complexes and is recognized by an anti-CR1 mAb (E11). Human erythrocytes express the type 1 CR (CR1), the most common form being 220,000 M(r) and consisting of 30 short consensus repeats (SCRs) for its entire extracellular region. The purpose of this investigation was to determine the structure of the 75,000 M(r) chimpanzee E-CR. A chimpanzee cell line was identified that expressed a 220,000 M(r) CR1, and a 75,000 M(r) molecule that was recognized by E11 and could bind human C3i. Utilizing this cell line, chimpanzee CR1 cDNA was amplified in overlapping segments by the PCR, using primer pairs specific for various regions of human CR1 cDNA. Direct sequencing of the PCR-amplified products revealed 6044 nucleotides encoding the entire 220,000 M(r) chimpanzee CR1. This nucleotide sequence was 98.8% homologous to that of the human 220,000 M(r) CR1. Amplification using a CR1 primer from the signal peptide and from the cytoplasmic region yielded a 1985-bp PCR product, termed CR1a. The CR1a sequence was identical with the sequence encoding SCRs 1 to 6, SCRs 28 to 30, and the transmembrane and cytoplasmic regions of chimpanzee CR1. This alternatively spliced product of chimpanzee CR1 would encode a protein of 71,000 peptide m.w. with six potential N-glycosylation sites. Amplification employing a CR1 primer from SCR 1 and from the 3' untranslated region yielded a second PCR product of 1731 bp. This sequence, termed CR1b, encoded eight SCRs, followed by a hydrophobic region that ended in a stop codon. The first six SCRs of CR1b were closer in homology to the first six SCRs of a human CR1-like genomic sequence (97.4%) than to those of the chimpanzee CR1 (94.8%). Taken together, these sequence data suggest that the 75,000 M(r) chimpanzee E-CR is encoded by CR1a, an alternative splice variant of chimpanzee CR1. The CR1b is presumably derived from an RNA species related to the CR1-like genomic sequence previously described only in humans.