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.

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.

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.

[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.

[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.

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.

[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.

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.

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.

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.

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.

Effects of immune complex formation and complement activation on circulating platelets in the primate.

Primate platelets are different from rodent and rabbit platelets in that they do not express receptors for C3a or C5a or immune adherence receptors. This study assessed the effects of immune complex (IC)-induced complement activation on primate platelets in the circulation. Cynomolgus monkeys (CYN, N = 4) immunized to bovine gamma globulin (BGG) were infused with BGG over 5 min to induce acute intravascular IC formation and complement activation. The studies were carried out under normal complement conditions (N = 12), partial complement inhibition (CAB-2 treated, N = 3), or total complement inhibition (CVF treated, N = 1). Under normal complement conditions, BGG infusion increased C3a levels from undetectable to an average of 11.9 +/- 2.6 micrograms/ml. At this time, decreases occurring in both circulating neutrophils (85 +/- 6%) and monocytes (78 +/- 6%) were significantly greater than decreases in circulating platelets (13 +/- 3%, p < 0.001). Partial complement inhibition had an equivocal effect on the BGG-induced changes in circulating leukocytes, while total complement inhibition abrogated these changes. In contrast, platelet changes were unaffected by complement inhibition. We conclude that, compared to circulating leukocytes, circulating platelets are insensitive to intravascular complement activation induced by IC in the nonhuman primate. These results contrast with previous studies in rodents which demonstrate strong effects of IC-induced intravascular complement activation on both circulating neutrophils and platelets.

Effect of enalapril therapy on glomerular accumulation of immune complexes and mesangial matrix in experimental glomerulonephritis in the nonhuman primate.

The present study is a prospective, controlled, blinded trial of enalapril therapy in experimental immune complex (IC)-mediated glomerulonephritis (GN) in the nonhuman primate (cynomolgus monkey [CYN]). Two groups of CYNs were studied: those with established GN (study A) and those in which GN was being induced (study B). In study A, 12 CYNs had GN established by 8 or 10 weeks of daily intravenous infusion of bovine gamma-globulin (BGG). These CYNs were then assigned to either 4 weeks of daily oral enalapril therapy (n = 6) or daily oral placebo therapy (n = 6). The daily BGG infusions were continued during the 4 weeks of enalapril or placebo therapy. At the start of the enalapril/placebo protocol, the two groups were similar with respect to proteinuria and level of precipitating antibody to BGG, which determined the daily BGG dose. Renal biopsy was performed in each CYN at the start and end of the 4-week period of enalapril/placebo protocol. In study B, 15 normal CYNs were immunized to BGG over a period of 4 weeks. The CYNs were then assigned to daily oral enalapril therapy (n = 8) or placebo therapy (n = 7) based on level of precipitating antibody to BGG. At this point, daily intravenous BGG was begun along with daily enalapril or placebo for 8 weeks. Renal biopsy was performed in each CYN before and at the end of this 8-week period. In study A, enalapril therapy was associated with a significant decrease in mesangial matrix volume (mean change, -27.7%; P = 0.031) and a trend toward decreased mesangial matrix deposits (mean change, -34.1%; P = 0.188). By contrast, in CYNs receiving placebo therapy, mesangial matrix volume increased compared with the enalapril group (P = 0.002) and mesangial deposits were unchanged. In study B, both the enalapril and placebo groups showed significant increases in mesangial matrix volume, mesangial deposits, mesangial cell volume, and capillary wall deposits during the 8 weeks of daily BGG infusion. However, none of the differences between the groups achieved statistical significance. Changes in mesangial cell volume and capillary wall deposits were also evaluated in study A and study B, but were not found to be different between the enalapril and placebo groups. In both study A and study B, blood pressure was lower in the enalapril groups. In conclusion, in the initial phase of IC-GN induction (0 to 8 weeks), enalapril therapy does not significantly influence the glomerular accumulation of mesangial matrix or immune deposits. However, in established IC-GN (after 8 weeks of GN induction), enalapril therapy significantly decreases the further accumulation of mesangial matrix and may decrease the further accumulation of mesangial deposits. Whether this benefit of enalapril therapy was related to lower blood pressure or to other effects of angiotensin-converting enzyme (ACE) inhibition was not determined in this study.

The baboon erythrocyte complement receptor is a glycophosphatidylinositol-linked protein encoded by a homologue of the human CR1-like genetic element.

The human erythrocyte CA receptor (E-CR) is the type 1 complement receptor (CR1), the most common form of which is a 220,000 Mr integral membrane glycoprotein composed of 30 short consensus repeats (SCRs). The E-CR of many nonhuman primates is a smaller receptor of unknown genetic origin. Recently, we identified a chimp cDNA, termed CR1b, which represented transcription of a homologue of the human genetic element, CR1-like. The purpose of this study was to identify CR1b in the baboon and, if present, determine whether it encodes the 65,000 Mr baboon E-CR. Baboon bone marrow cDNA was amplified by PCR using primers specific for the signal peptide-encoding region of human CR1 and the 3' region of chimp CR1b. This amplification yielded a CR1b sequence predicted to encode seven SCRs followed by a hydrophobic region, with an N terminus homologous to the N terminus of baboon E-CR. Expression of baboon CR1b yielded a membrane protein that reacted with an anti-CR1 mAb, was identical in size to baboon E-CR, and, like baboon E-CR, could bind baboon C3 linked to activated thiol-Sepharose (C3i-ATS), but not human C3i-ATS. Phosphatidylinositol-specific phospholipase C (PIPLC) released CR1b from Chinese hamster ovary cells and E-CR from baboon erythrocytes, demonstrating that both of these proteins are glycophosphatidylinositol linked to the membrane. Thus, the data indicate that baboon CR1b, a homologue of the human CR1-like genetic element, encodes a glycophosphatidylinositol-linked protein that is the baboon E-CR.