[Early results of left ventricular assist device implantation for the treatment of heart failure].

Twenty-four male patients who underwent left ventricular assist device (LVAD) implantation due to advanced heart failure in Union Hospital, Fujian Medical University from June 2019 to June 2022 were retrospectively included. The age of patients was 32-61 (48.4±8.4) years. Everheat-Ⅰ, HeartCon and Corheart 6 left ventricular assist systems were used in 10, 6 and 8 cases, respectively. All patients were discharged successfully without mechanical failure, thrombosis or secondary thoracotomy for hemostasis. Early postoperative hemodynamics were significantly improved, left ventricular systolic diameter was reduced, left ventricular ejection fraction was gradually improved, and no hemolysis occurred. The patients were followed up for 3 to 39 (17.9±8.6) months, the cardiac function was restored to grade Ⅰ to Ⅱ, and the 6-minute walking test distance increased significantly. Therefore, satisfactory early results can be achieved with left ventricular assist device implantation for the treatment of heart failure.

The new-generation proteasome inhibitor oprozomib increases the sensitivity of cervical cancer cells to cisplatin-induced apoptosis.

This study aimed to evaluate the anti-tumor effect of a new generation of protease inhibitor, oprozomib (OPZ), used alone and in combination with cisplatin, also called CDDP, on cervical cancer. Five different types of cervical cancer cell lines - HeLa, Caski, HeLa-CDDP, C33a, and SiHa - and one nontransformed cervical cell line - HaCaT -were treated with OPZ alone or in combination with cisplatin. The inhibitory effects of OPZ and cisplatin on the proliferation of cervical cancer cells were then analyzed using cytotoxicity tests, flow cytometry, and Western blotting. It was found that OPZ alone or in combination with cisplatin can reduce the proliferation of the five types of cancer cells by enhancing the lysis of caspase-3 and PARP and inducing cancer cell apoptosis. In the combined treatment, OPZ was found to inhibit the degradation of inhibitory factor κB alpha induced by cisplatin, thereby inhibiting the activation of NF-κB, which causes cisplatin resistance, and enhancing the sensitivity of the tumor cells to cisplatin. Moreover, OPZ promoted the phosphorylation of the apoptosis signaling pathway JNK that was activated by cisplatin, thereby inducing tumor cell apoptosis. These findings provide a theoretical basis for the clinical use of OPZ alone and in combination with cisplatin in the treatment of cervical cancer.

Element Specificity of Transient Extreme Ultraviolet Magnetic Dichroism.

In this work we combine theory and experiment to study transient magnetic circular dichroism (TRMCD) in the extreme ultraviolet spectral range in bulk Co and CoPt. We use the ab initio method of real-time time-dependent density functional theory to simulate the magnetization dynamics in the presence of short laser pulses. From this we demonstrate how TRMCD may be calculated using an approximation to the excited-state linear response. We apply this approximation to Co and CoPt and show computationally that element-specific dynamics of the local spin moments can be extracted from the TRMCD in the extreme ultraviolet energy range, as is commonly assumed. We then compare our theoretical prediction for the TRMCD for CoPt with experimental measurement and find excellent agreement at many different frequencies including the M_{23} edge of Co and N_{67} and O_{23} edges of Pt.

[Gastric adenocarcinoma with enteroblastic differentiation and elevated serum alpha fetoprotein].

Objective: To study the proportion and clinicopathological characteristics of gastric adenocarcinoma with enteroblastic differentiation (GAED) in gastric cancers showing an elevated serum alpha fetoprotein(AFP). Methods: A total of 724 resected gastric adenocarcinomas were collected from 2008 to 2018 at the 904 Hospital of Joint Service Support Force, and cases with pre-operative serum AFP>10 µg/L were screened. From the cases with elevated serum AFP, GAED cases were further evaluated based on morphology. Then the clincopathological features and immunohistochemical phenotypes of GAED were reviewed. In addition, the amplification of HER2 gene was detected with fluorescence in situ hybridization(FISH). When overall survival (OS) and progression-free survival (PFS) of GAED were analyzed, 289 cases ordinary gastric adenocarcinoma with normal serum AFP were employed as a control. Results: The percentage of GAED was 44% (11/25) in gastric cancers with elevated serum AFP. GAED was histologically tubular or papillary with clear cytoplasm, and some GAED cases showed cystadenoid structure similar to embryo sac (5 cases), homogeneous eosinophilic granules (4 cases) and intragland ulareosinophilic material (6 cases). All 11 GAED cases had lymph node metastasis. Liver metastasis and vascular thrombus were observed in 2 cases and 5 cases respectively. GAED was immunohistochemically positive for CDX2 (11/11), CD10 (8/11) and MUC2(3/11), which were intestinal epithelium differentiation markers. Meanwhile, primitive markers SALL4 (8/11), GPC3 (7/11) and AFP (5/11) were also expressed in GAED, and HER2 gene amplification was found in 3 cases (3/11) of GAED. Lastly, the PFS of GAED were significantly shorter than that of the control group (P=0.02), while OS was not statistically different between these two groups (P=0.99). Conclusions: Patients with GAED usually have a higher rate of elevated serum AFP in gastric adenocarcinoma, and the cancer exhibites features of both intestinal and primitive differentiation. As GAED is highly invasive, the prognosis of GAED may be poor. For GAED, the diagnosis of well-differentiated or moderately-differentiated adenocarcinoma should be avoided, because this diagnosis leads to underestimated malignant potential.

[Mechanism of nano-indium-tin oxide inducing pulmonary alveolar proteinosis in Sprague-Dawley rats].

Objective: To investigate the pathogenesis of pulmonary alveolar proteinosis in rats induced by nano-indium-tin oxide exposure, and to provide a basis for further determining the limit of occupational exposure to indium and developing related protection measures. Methods: In August 2018, a total of 40 specific pathogen-free Sprague-Dawley rats, with an age of 6-8 weeks and a body weight of (200±10) g, were randomly divided into control group, low-dose group (1.2 mg/kg) , middle-dose group (3 mg/kg) , and high-dose group (6 mg/kg) , with 10 rats in each group. After 1 week of routine feeding, the rats were given non-exposed intratracheal instillation twice every week, with an interval of 3 days, for 12 consecutive weeks. Body weight was measured every week during exposure to observe the change in body weight; The rats were anesthetized and sacrificed by chloral hydrate after the exposure ended, and lung tissue and serum were collected; Hematoxylin-eosin staining and periodic acid-Schiff (PAS) staining were performed for lung tissue to observe pathological results; Inductively coupled plasma mass spectrometry was used to measure the serum level of indium; ELISA was used to measure the levels of surfactant protein A (SP-A) , surfactant protein D (SP-D) , and the type II alveolar cell surface antigen Krebs von den Lungen-6 (KL-6) in lung tissue and the serum level of granulocyte-macrophage colony-stimulating factor (GM-CSF) . Results: The pathological results showed that the rats in the control group had basically complete alveolar structure, and after intratracheal instillation of nano indium-tin oxide, uniform, eosinophilic, and unstructured granular substances were observed in the alveolar space of the low-, middle-, and high-dose exposure groups, with macrophage proliferation and an increase in macrophages, especially in the high-dose group. Negative PAS staining was observed in the control group, while substances with positive PAS staining were observed in lung tissue in each exposure group. The three exposure groups had a significantly higher serum level of indium than the control group (P<0.05) . Compared with the control group, the three exposure groups had significant increases in SP-A, SP-D, and KL-6 in lung tissue and a significant reduction in GM-CSF in serum (P<0.05) . Conclusion: Pulmonary alveolar proteinosis in rats may be associated with the destruction of alveolar macrophages caused by nano-indium-tin oxide and the aggregation of pulmonary surfactants due to disorders in the metabolism and clearance of pulmonary surfactants by macrophages.

[Altered serum cytokine expression profile in systemic sclerosis and its regulatory mechanisms].

OBJECTIVE: To analyze the expression profile of serum cytokines in patients with systemic sclerosis (SSc) and explore its possible regulatory mechanisms. METHODS: Serum and DNA of peripheral blood mononuclear cells were collected from 30 SSc patients and 80 normal controls (NCs). According to the presence or absence of interstitial lung disease (ILD) in SSc, the patients were divided into SSc with ILD group and SSc without ILD group. According to the degree of skin involvement, the patients were divided into diffuse systemic scleroderma (dcSSc) group and limited systemic scleroderma (lcSSc) group. According to the presence of anti-topoisomerase-1 antibody (anti-Scl-70 antibody) in the serum of patients with SSc, they were divided into SSc Scl-70 (+) group and SSc Scl-70 (-) group. 27 cytokines in serum were detected by Luminex MAGPIX detection system and Bio-Plex Pro Human Cytokine 27-plex Assay kit: interleukin-1ß (IL-1ß), interleukin-1 receptor antagonist (IL-1ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12P70, IL-13, IL-15, IL-17, basic fiber growth factor (BASIC FGF), eotaxin, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interferon-γ (IFN-γ), interferon-gamma induced protein 10(IP-10), monocyte chemotactic protein 1(MCP-1), macrophage inflammatory protein-1α (MIP-1α), macrophage inflammatory protein 1ß(MIP-1ß), platelet-derived growth factor BB (PDGF-BB), regulated on activation in normal T-cell expressed and secreted (RANTES), tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor(VEGF). Methylation sites were detected by Illumina 450K methylation chip. RESULTS: Compared with NCs group, the expression of 12 cytokines (BASIC FGF, eotaxin, G-CSF, GM-CSF, IFN-γ, IL-1ß, IL-1ra, IL-6, IP-10, MCP-1, TNF-α and RANTES) in the SSc group significantly increased (P<0.05), IL-5 was decreased expression in the SSc group (P<0.05), there was no significant difference in the expressions of the other 14 cytokines. Compared with lcSSc group, 9 cytokines (eotaxin, IL-5, MCP-1, IL-2, RANTES, IL17A, IL-8, MIP-1ß and PDGF-BB) increased in dcSSc group, but there was no significant difference. Compared with SSc without ILD group, IL-15 increased in SSC with ILD group [18.2 (172.97) ng/L vs. 2.03(0.05) ng/L, P<0.05]. Compared with SSc Scl-70 (-) group, the expression of IP-10 decreased in SSc Scl-70 (+) group [1 030 (2 196.6) ng/L vs. 1 878 (2 964) ng/L, P<0.05]. The correlation analysis of serum cytokines with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) showed that IL-6 was positively correlated with ESR (r =0.04, P= 0.017), MCP-1 (r=0.49, P=0.043) and MIP-1ß (r=0.41, P=0.007) positively correlated with CRP. By analyzing the changes of methylation sites of cytokines, it was found that cg17744604 in IL-10 TSS1500 region, cg06111286 in IL-12P70 TSS200 region, cg07935264 in IL-1ß TSS200 region, cg01467417 in IL-1ra TSS1500 region, cg03989987 in IL-1ra 5'UTR region and cg21099624 in VEGF TSS200 region were all hypomethylated. CONCLUSION: There were different cytokines expression profiles in the serum of SSc patients, and the altered cytokines were correlected with the degree of skin damage and pulmonary fibrosis. Many cytokines were regulated by methylation.

[Contrast-enhanced CT and texture analysis of mass-forming pancreatitis and cancer in the pancreatic head].

Objective: To explore the value of contrast-enhanced CT combined with texture analysis in differentiating pancreatic cancer from mass-forming pancreatitis in pancreatic head. Methods: A retrospective study collected 21 patients with pancreatic head mass-forming pancreatitis confirmed by surgery or biopsy and 47 patients with pancreatic ductal adenocarcinoma confirmed by surgery. The patients visited the Affiliated Hospital of Nanjing University of Chinese Medicine and the First Affiliated Hospital of Wannan Medical College between January 2014 and December 2017. Gender, age and CT findings were collected. The parenchymal phase was selected for texture analysis. The minimum absolute shrinkage and selection operator (LASSO) method was applied for dimensionality reduction.Two independent sample t-tests or Mann-Whitney U test were used for continuous variables based on the Shapiro-Wilks normality test results. Categorical variables were tested by Chi-square or Fisher test. By multivariable regression analysis, CT findings, CT texture analysis, CT findings combined with texture analysis prediction models were established. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance of individual indicators and each prediction model. The Delong test was used to compare the area under the curve (AUC) of each model. Results: The CT findings prediction model consisted of CT value of lesion on pancreatic parenchymal phase and pancreatic duct penetrating sign. The texture analysis prediction model consists of root mean square and low grey level run emphasis_angle135. The AUC of them were not statistically different (Z=0.150,P>0.05). The combined predictive model had the better diagnostic performance (AUC 0.944, sensitivity 83.0%, specificity 95.2%, +LR 17.43, -LR 0.18) than CT sign prediction model (Z=2.008, P<0.05) and texture analysis prediction model(Z=2.236, P<0.05) were significantly different. Conclusions: The CT findings model and the texture analysis model have equivalent diagnostic performance in the differentiation of mass-forming pancreatitis and pancreatic cancer. The enhanced CT combined with texture analysis model has the best diagnostic efficiency and can further improve the diagnostic ability.

CdS nanoparticles of different lengths induce differential responses in some of the liver functions of mice.

Cadmium sulfide nanoparticles (CdS NPs) are one of important nanoparticle materials which are widely used in photoelectric production, but their potential health hazard to the liver is not clear. This study is aimed at exploring the possible mechanisms of liver injury induced by CdS NPs. Male mice were treated with nanoparticles of 110-130 nm and 80-100 nm cadmium sulfide. The main methods were based on detecting the vigor of superoxide dismutase (SOD) and glutathione (GSH), and content of malondialdehyde (MDA) in both blood and liver tissues as well as on observing the pathological changes in liver tissue. CdS NPs suppressed the activity of SOD and GSH, and increased the serum MDA content (p < 0.05); both effects were observed together in liver tissues of 80-100 nm group (p < 0.05) and were accompanied by an obviously inflammatory response. CdS NPs induced oxidative damage and inflammatory response in liver tissue, which may be an underlying mechanism for its pulmonary toxicity. Additionally, the toxicity of CdS NPs was closely related to the size of nanoparticles. Pathological results showed that the hepatotoxicity of shorter CdS NPs is greater than that of longer CdS NPs (Tab. 6, Fig. 3, Ref. 20).

Association between transcription factor 7-like 2 genetic polymorphisms and development of type 2 diabetes in a Chinese population.

We conducted a hospital-based case-control study to evaluate the relationship between the transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism and type 2 diabetes mellitus risk in a Chinese population. Genotyping of TCF7L2 rs7903146 was carried out using the polymerase chain reaction-restriction fragment length polymorphism method. A chi-square test revealed a statistically significant difference between the distributions of rs7903146 genotypes in type 2 diabetes mellitus patient and control groups (chi-square = 10.49, P = 0.005). Using unconditional logistic regression analysis, we observed that the TT genotype of this polymorphism was significantly correlated with increased risk of developing type 2 diabetes mellitus compared to the CC genotype [odds ratio (OR) = 2.31, 95% confidence interval (CI) = 1.33-4.04]. Furthermore, we found that the rs7903146 sequence variation was also significantly associated with susceptibility to this disease under dominant (OR = 1.58, 95%CI = 1.09-2.28) and recessive models  (OR = 2.11, 95%CI = 1.25-3.62). We conclude that the TCF7L2 rs7903146 genetic polymorphism is independently associated with the risk of developing type 2 diabetes mellitus under co-dominant, dominant, and recessive models.

Resistin as a potential marker of renal disease in lupus nephritis.

Systemic lupus erythematosus (SLE) and lupus nephritis (LN) have strong concomitance with cardiovascular disease that cannot be explained fully by typical risk factors. We examined the possibility that serum or urine expression of adipokines may act as biomarkers for LN, as these proteins have been associated previously with cardiovascular disease as well as SLE. Antibody arrays were performed on serum and urine from lupus patients and matched controls using a cross-sectional study design. From the initial array-based screening data of 15 adipokines, adiponectin, leptin and resistin were selected for validation by enzyme-linked immunosorbent assay (ELISA). Correlations were determined between adipokine expression levels and measures of disease activity or lupus nephritis. The expression of adiponectin and resistin was increased in both sera and urine from LN patients, while leptin was increased in LN patient sera, compared to matched controls. Serum resistin, but not urine resistin, was correlated with measures of renal dysfunction in LN. Serum resistin expression may be useful as a marker of renal dysfunction in patients with LN, although longitudinal studies are warranted. Further studies are necessary to determine if resistin has functional consequences in LN.

Correlation analysis of the PNPLA7 gene polymorphism and susceptibility to menstrual disorder.

We examined the correlation between PNPLA7 gene polymorphisms at the rs61754920 and rs11137410 loci and menstrual disorder in women of reproductive age in the Central Plain. Genomic DNA was extracted from peripheral blood; polymerase chain reaction-ligase detection reaction and SNaPshot genotyping were used to detect polymorphisms in the rs61754920 and rs11137410 gene loci, respectively. The results for the 2 loci in individuals of different blood types were statistically analyzed. The proportion of the AA homozygote at the rs61754920 locus in the PNPLA7 gene was the lowest, while the proportion of the CC homozygote at the rs11137410 locus in the PNPLA7 gene was the highest. There were no statistical differences in the frequency distribution of genotypes and alleles at the 2 loci between control and test groups. The frequency of the TT genotype at the rs11137410 locus in women with type O blood was significantly lower in the test group than in the control group. Frequencies of the C and T alleles were significantly different between the 2 groups. There may be an association between the PNPLA7 gene and type O blood or a combined effect of the 2 genes.

The factors influencing the occurrence of post-ischemic stroke depression and its relationship with the burden score of cerebral small vessel disease.

OBJECTIVE: This study explored the determinants of post-stroke depression (PSD) in ischemic stroke (AIS) patients and its association with the burden score of cerebral small vessel disease (CSVD). PATIENTS AND METHODS: We analyzed 374 AIS patients treated between January 2020 and January 2022. Patients were categorized into 90 with PSD and 284 without PSD, enabling an investigation into PSD risk factors and the CSVD-PSD relationship. RESULTS: There was no significant difference in health factors between PSD and non-PSD patients (p>0.05). However, significant disparities were noted in age, gender, initial Barthel Index (BI), Mini-Mental State Examination (MMSE) score, plasma fibrinogen, homocysteine, red cell distribution width, National Institutes of Health Stroke Scale (NIHSS) score, and CSVD burden score (p<0.05). Regression analysis indicated that these variables were pivotal PSD predictors (OR>1, p<0.05). Surprisingly, a positive correlation with PSD occurrence was found for age, NIHSS score, plasma fibrinogen, homocysteine levels, red cell distribution width, CSVD burden score (r=0.565, 0.615, 0.482, 0.514, 0.572, 0.608, respectively; p<0.05). Meanwhile, the MMSE score and BI index were inversely related to PSD onset (r=-0.604, -0.590; p<0.05). The ROC curve analysis of the combination model based on MMSE, NIHSS and CSVD score revealed an AUC of 0.926 and Youden's index of 0.744. CONCLUSIONS: Age, MMSE score, BI index, NIHSS score, plasma fibrinogen concentration, homocysteine level, red blood cell distribution width, and CSVD burden score are all major influencing factors in the occurrence of PSD. The combination model based on MMSE, NIHSS, and CSVD scores presented a valuable approach to predicting PSD.

Elevated IgG autoantibody production in oligoarticular juvenile idiopathic arthritis may predict a refractory course.

OBJECTIVES: Although oligoarticular juvenile idiopathic arthritis (oJIA) is considered to carry the best prognosis among the JIA subtypes, many children evolve to a chronic course. A few studies have identified clinical risk factors for disease extension, and recent studies have evaluated synovial fluid markers. However, the only biological marker from the serum studied to date is the anti-nuclear antibody (ANA), regarding which there is mixed data regarding prognosis. No studies have evaluated whether additional autoantibodies may affect the articular prognosis of oJIA. METHODS: Microarrays containing candidate autoantigens were printed on slides, which were used to profile 36 children with oJIA and 18 controls. Unsupervised cluster analysis was used to identify distinct subgroups of JIA patients. Response to therapy after a mean interval of 4.9 months was evaluated. RESULTS: Cluster analysis revealed two subgroups of oJIA patients, with identical clustering observed when children with onset over age six were excluded. Cluster 1 had higher levels of multiple autoantibodies compared to both cluster 2 as well as controls, including antibodies against several extracellular matrix (ECM) and nuclear antigens. Although the two patient clusters were similar with respect to clinical features and treatment decisions, children in cluster 1 were less likely to have attained remission by the follow-up visit. CONCLUSIONS: Antibodies against ECM and possibly other antigens may identify a sub-group of children with oJIA who will require more aggressive therapy to attain control of the arthritis.

Potential role of adenosine monophosphate-activated protein kinase in regulation of energy metabolism in dairy goat mammary epithelial cells.

The 5'-adenosine monophosphate-activated protein kinase (AMPK) is an energy sensor that regulates cellular metabolism. 5'-Adenosine monophosphate-activated protein kinase controls glucose and lipid metabolism in skeletal muscle, liver, and adipose tissues. The aim of this study was to investigate the effects of AMPK on glucose and lipid metabolism in dairy goat mammary epithelial cells. Treatment of mammary epithelial cells with an AMPK activator (5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside) dramatically increased glucose uptake and glucose transporter-1 mRNA abundance, and decreased levels of glycogen synthase 1 mRNA. Activation of AMPK also induced an increase in carnitine palmitoyl transferase 1 mRNA and decreases in fatty acid synthase and acetyl-CoA carboxylase 1 mRNA. These results suggest that AMPK is involved in the regulation of energy metabolism in dairy goat mammary epithelial cells.

Interferon signature gene expression is correlated with autoantibody profiles in patients with incomplete lupus syndromes.

Interferon (IFN) signature genes have been shown to be expressed highly in peripheral blood of patients with systemic lupus erythematosus (SLE), especially in the presence of active disease. However, the expression of this gene signature in individuals with incomplete forms of lupus and the pathogenic relationship between IFN signature genes and autoantibody production have not been explored fully. In the present study, we examined the gene expression and autoantibody profiles of patients diagnosed with incomplete lupus erythematosus (ILE) to determine correlations of the gene expression signature with autoantibody production. Gene expression analysis was carried out on the 24K Illumina Human Refseq-8 arrays using blood samples from 84 subjects, including patients with SLE (n = 27) or ILE (n = 24), first-degree relatives (FDR) of these patients (n = 22) and non-autoimmune control (NC) individuals (n = 11). Autoantibody expression was measured using standard immunoassays and autoantigen proteomic arrays. Up-regulation of a set of 63 IFN signature genes was seen in 83% of SLE patients and 50% of ILE patients. High levels of IFN gene expression in ILE and SLE showed significant correlations with the expression of a subset of IgG autoantibodies, including chromatin, dsDNA, dsRNA, U1snRNP, Ro/SSA, La/SSB, topoisomerase I and Scl 70, while low IFN levels were correlated with immunoglobulin (Ig)M autoreactivity. These studies suggest that in patients with ILE the IFN gene expression signature may identify a subset of these individuals who are at risk for disease progression. Furthermore, high levels of alpha IFN may promote autoantibody class-switch from IgM to the more pathogenic IgG class.

The relationship between endoplasmic reticulum stress and liver function, insulin resistance and vascular endothelial function in patients with non-alcoholic fatty liver disease.

OBJECTIVE: The aim of the study was to investigate the relationship between ER stress and liver function, insulin resistance and vascular endothelial function in patients with non-alcoholic fatty liver disease. PATIENTS AND METHODS: A total of 95 patients with non-alcoholic fatty liver disease were selected. They were admitted to our hospital from November 2016 to January 2019. A total of 90 cases of obese patients without fatty liver were selected as control group during the same period. The levels of ER stress marker protein were compared between the two groups, and the relationship between ER stress and liver function, insulin resistance, and vascular endothelial function was analyzed. RESULTS: The protein level of ER stress markers in the test group was significantly higher than that in the control group (p<0.05). The liver function index and insulin resistance level were significantly higher than those in the control group (p<0.05). The level of vascular endothelial function was significantly lower than that of the control group (p<0.05). Pearson correlation analysis showed that ER stress marker protein was positively correlated with liver function and insulin resistance (p<0.05), while ER marker protein was negatively correlated with vascular endothelial function (p<0.05). CONCLUSIONS: Liver function and insulin resistance are closely related to ER stress in patients with non-alcoholic fatty liver disease. Insulin resistance is one of the factors inducing and aggravating endothelial dysfunction.

The lupus-susceptibility gene kallikrein downmodulates antibody-mediated glomerulonephritis.

Sle3 is a NZM2410/NZW-derived lupus-susceptibility interval on murine chromosome 7, which is associated with spontaneous lupus nephritis (SLN), and also anti-GBM-induced glomerulonephritis (GN). The tissue kallikrein gene cluster is located within the Sle3 interval and constitutes potential candidate genes for this locus. We have recently reported that renal kallikrein expression was upregulated by anti-GBM antibody challenge in a strain-specific manner and that it was significantly underexpressed in the anti-GBM-sensitive strains, including B6.Sle3. Further sequencing and functional studies reported earlier provided evidence that kallikreins could constitute disease genes in lupus. In this report, we have used an adenoviral vector to deliver the klk1 gene to B6.Sle3 congenics to directly test if kallikreins might have a protective effect against anti-GBM-induced nephritis. Our data show that klk1 gene delivery ameliorated anti-GBM-induced nephritis in B6.Sle3 congenics. Taken together with earlier studies, these findings indicate that kallikreins play an important protective role in autoantibody-initiated GN and could constitute potential candidate genes for anti-GBM-induced GN and SLN.

Evaluation of C1q genomic region in minority racial groups of lupus.

Complement cascade plasma proteins play a complex role in the etiopathogenesis of systemic lupus erythematosus (SLE). Hereditary C1q deficiency has been strongly related to SLE; however, there are very few published SLE studies that evaluate the polymorphisms of genes encoding for C1q (A, B and C). In this study, we evaluated 17 single nucleotide polymorphisms (SNPs) across 37 kb of C1QA, C1QB and C1QC in a lupus cohort of individuals of the African-American and Hispanic origin. In a case-only analysis, a significant association at multiple SNPs in the C1QA gene was detected in African Americans with kidney nephritis (best P=4.91 x 10(-6)). In addition, C1QA was associated with SLE in African Americans with a lack of nephritis and accompanying photosensitivity when compared with that in normal controls (P=6.80 x 10(-6)). A similar trend was observed in the Hispanic subjects (P=0.003). Quantitative analysis showed that some SNPs in C1q genes might be correlated with C3 complement levels in an additive model among African Americans (best P=0.0001). The C1QA gene is associated with subphenotypes of lupus in the African-American and Hispanic subjects. Further studies with higher SNP densities in this region and other complement components are necessary to elucidate the complex genetics and phenotypic interactions between complement components and SLE.

Replication of the BANK1 genetic association with systemic lupus erythematosus in a European-derived population.

Systemic lupus erythematosus (SLE) is an autoimmune disease with highly variable clinical presentation. Patients suffer from immunological abnormalities that target T-cell, B-cell and accessory cell functions. B cells are hyperactive in SLE patients. An adapter protein expressed in B cells called BANK1 (B-cell scaffold protein with ankyrin repeats) was reported in a previous study to be associated with SLE in a European population. The objective of this study was to assess the BANK1 genotype-phenotype association in an independent replication sample. We genotyped 38 single nucleotide polymorphisms (SNPs) in BANK1 on 1892 European-derived SLE patients and 2652 European-derived controls. The strongest associations with SLE and BANK1 were at rs17266594 (corrected P-value=1.97 x 10(-5), odds ratio (OR)=1.22, 95% CI 1.12-1.34) and rs10516487 (corrected P-value=2.59 x 10(-5), OR=1.22, 95% CI 1.11-1.34). Our findings suggest that the association is explained by these two SNPs, confirming previous reports that these polymorphisms contribute to the risk of developing lupus. Analysis of patient subsets enriched for hematological, immunological and renal ACR criteria or the levels of autoantibodies, such as anti-RNP A and anti-SmRNP, uncovers additional BANK1 associations. Our results suggest that BANK1 polymorphisms alter immune system development and function to increase the risk for developing lupus.