The Cytokines CXCL10 and CCL2 and the Kynurenine Metabolite Anthranilic Acid Accurately Predict Patients at Risk of Developing Dengue With Warning Signs.

BACKGROUND: The resolution or aggravation of dengue infection depends on the patient's immune response during the critical phase. Cytokines released by immune cells increase with the worsening severity of dengue infections. Cytokines activate the kynurenine pathway (KP) and the extent of KP activation then influences disease severity. METHODS: KP metabolites and cytokines in plasma samples of patients with dengue infection (dengue without warning signs [DWS-], dengue with warning signs [DWS+], or severe dengue) were analyzed. Cytokines (interferon gamma [IFN-É£], tumor necrosis factor, interleukin 6, CXCL10/interferon-inducile protein 10 [IP-10], interleukin 18 [IL-18], CCL2/monocyte chemoattractant protein-1 [MCP-1], and CCL4/macrophage inflammatory protein-1beta [MIP-1ß] were assessed by a Human Luminex Screening Assay, while KP metabolites (tryptophan, kynurenine, anthranilic acid [AA], picolinic acid, and quinolinic acid) were assessed by ultra-high-performance liquid chromatography and Gas Chromatography Mass Spectrophotometry [GCMS] assays. RESULTS: Patients with DWS+ had increased activation of the KP where kynurenine-tryptophan ratio, anthranilic acid, and picolinic acid were elevated. These patients also had higher levels of the cytokines IFN-É£, CXCL10, CCL4, and IL-18 than those with DWS-. Further receiver operating characteristic analysis identified 3 prognostic biomarker candidates, CXCL10, CCL2, and AA, which predicted patients with higher risks of developing DWS+ with an accuracy of 97%. CONCLUSIONS: The data suggest a unique biochemical signature in patients with DWS+. CXCL10 and CCL2 together with AA are potential prognostic biomarkers that discern patients with higher risk of developing DWS+ at earlier stages of infection.

[Pathological study on the relationship between nucleic acid oxidative stress and heart failure with preserved ejection fraction in patients aged over 85 years].

Objective: To investigate the level of nucleic acid oxidation in myocardial tissue of patients aged over 85 with heart failure with preserved ejection fraction (HFpEF) and the correlation with myocardial amyloid deposition. Methods: This was a retrospective case-control study. Data of patients≥85 years old who underwent systematic pathological autopsy in Beijing Hospital from 2003 to 2017 were retrospectively collected. Twenty-six patients were included in the HFpEF group and 13 age-and sex-matched patients who had not been diagnosed with heart failure and died of non-cardiovascular diseases served as the control group. The left ventricular myocardium slices of both groups were semi-quantitatively analyzed using immunohistochemical staining of 8-oxidized guanine riboside (8-oxo-G) and 8-oxidized guanine deoxyriboside (8-oxo-dG) to evaluate the oxidation of RNA and DNA in cardiomyocytes. Using the median of the mean absorbance value of 8-oxo-G immunohistochemical staining as the cut-off value, patients were divided into high-absorbance group and low-absorbance group. Congo red staining was used to compare myocardial amyloid deposition between the two groups. Results: The mean age of patients in HFpEF group was (91.8±3.7) years, 24 (92.3%) were males. The mean age of patients in control group was (91.7±3.7) years old, 11 (84.6%) were males. The median mean optical absorbance value of 8-oxo-G immunohistochemical staining of myocardium was significantly higher in HFpEF patients than in control group (0.313 8 (0.302 2, 0.340 6) vs. 0.289 2 (0.276 7, 0.299 4), Z=-3.245, P=0.001). The median mean absorbance value of 8-oxo-dG immunohistochemical staining of myocardial tissue was similar between the two groups (0.300 0 (0.290 0, 0.322 5) vs. 0.300 0 (0.290 0, 0.320 0), Z=-0.454, P=0.661). Proportion of patients with moderate and severe cardiac amyloid deposition was significantly higher in the high-absorbance group than in the low-absorbance group ((85.0%, 17/20) vs. (31.6%, 6/19), P=0.001). Conclusion: The RNA oxidation degree of myocardium in HFpEF patients is higher than that in elderly people without heart failure. Degree of myocardial amyloid deposits is higher in patients with high levels of RNA oxidation.

Systemic perturbations of the kynurenine pathway precede progression to dementia independently of amyloid-ß.

Increasing evidence suggests that kynurenine pathway (KP) dyshomeostasis may promote disease progression in dementia. Studies in Alzheimer's disease (AD) patients confirm KP dyshomeostasis in plasma and cerebrospinal fluid (CSF) which correlates with amyloid-ß and tau pathology. Herein, we performed the first comprehensive study assessing baseline levels of KP metabolites in participants enrolling in the Australian Imaging Biomarkers Flagship Study of Aging. Our purpose was to test the hypothesis that changes in KP metabolites may be biomarkers of dementia processes that are largely silent. We used a cross-sectional analytical approach to assess non-progressors (N = 73); cognitively normal (CN) or mild cognitive impairment (MCI) participants at baseline and throughout the study, and progressors (N = 166); CN or MCI at baseline but progressing to either MCI or AD during the study. Significant KP changes in progressors included increased 3-hydroxyanthranilic acid (3-HAA) and 3-hydroxyanthranilic acid/anthranilic acid (3-HAA/AA) ratio, the latter having the largest effect on the odds of an individual being a progressor (OR 35.3; 95% CI between 14 and 104). 3-HAA levels were hence surprisingly bi-phasic, high in progressors but low in non-progressors or participants who had already transitioned to MCI or dementia. This is a new, unexpected and interesting result, as most studies of the KP in neurodegenerative disease show reduced 3-HAA/AA ratio after diagnosis. The neuroprotective metabolite picolinic acid was also significantly decreased while the neurotoxic metabolite 3-hydroxykynurenine increased in progressors. These results were significant even after adjustment for confounders. Considering the magnitude of the OR to predict change in cognition, it is important that these findings are replicated in other populations. Independent validation of our findings may confirm the utility of 3-HAA/AA ratio to predict change in cognition leading to dementia in clinical settings.

[Recommendations for management of antiphospholipid syndrome in China].

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder with vascular, obstetric, and hematological manifestations associated with thrombotic and inflammatory mechanisms orchestrated by antiphospholipid (aPLs) antibodies. Current clinical practice in APS is highly variable duo to lack of high quality of evidence. Here, Chinese Rheumatology Association developed recommendations for management of APS in China. The recommendations cover the early diagnosis, disease evaluation, thrombotic risk assessment, and treatment.

Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia.

The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-D-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes,  leading to DLPFC volume loss, and attention impairment in schizophrenia.

[A comparative study of transperitoneal transmesenteric approach versus paracolic sulci approach laparoscopic adrenal tumorectomy for treatment of primary hyperaldosteronism on left side].

Objective: To compare the therapeutic effect of transperitoneal transmesenteric approach versus paracolic sulci approach laparoscopic adrenal tumorectomy for treatment of left-sided primary hyperaldosteronism. Methods: From January 2017 to July 2019, the clinical data of 70 patients with left-sided primary hyperaldosteronism (PHA) who underwent surgery in the First Hospital of Lanzhou University and five other hospitals in Gansu Province were retrospectively analyzed. There are 43 male and 27 female patients. Among them,28 patients were performed transperitoneal transmesenteric approach laparoscopic adrenal tumorectomy and 42 patients were performed transperitoneal paracolic sulci approach laparoscopic adrenal tumorectomy. The general information and perioperative data of the two groups were compared. Results: All 70 cases of surgery were successfully completed. As compared with the paracolic sulci approach group, the operation time was significantly shorter in the transmesenteric approach group[(26.7±8.8)vs (38.9±7.1)min,P<0.001)], and the estimated blood loss was less in the transmesenteric approach group[45(30,50) vs 50(40,60)ml,P=0.042]. There was no statistically significant difference in the postoperative hospitalization days between the two groups[(4.4±1.0)vs(4.5±1.0)d, P=0.669)]. The electrolytes and aldosterone to renin ratio returned to a healthy level in the postoperative one month, and the blood pressure also returned to a healthy level in 53 (75.7%) patients. Conclusion: Transperitoneal transmesenteric approach laparoscopic adrenal tumorectomy is safe and feasible, with a short operation time and relatively less estimated blood loss.

[Clinical characteristics of heart failure with recovered ejection fraction].

Objective: To summarize the clinical characteristics of heart failure patients with recovered ejection fraction (HFrecEF) and identify variables capable of predicting left ventricular ejection fraction (LVEF) recovery. Methods: This case control study included patients with heart failure, who admitted to Department of Cardiology of Beijing Hospital from January 1, 2009 to December 31, 2017. The patients were divided into 3 groups based on the baseline LVEF and changes of LVEF: heart failure with reduced ejection fraction (HFrEF, baseline LVEF≤40%, follow-up LVEF≤40% or follow-up LVEF>40% but LVEF increase<10% from baseline), HFrecEF(baseline LVEF≤40%, follow-up LVEF>40% and increase≥10% from baseline), and heart failure with preserved ejection fraction (HFpEF, baseline LVEF>40%). Clinical data were collected and endpoint events (all-cause death, cardiovascular death and sudden death) were recorded. The Log-rank test was used to evaluate the differences of terminal events in different groups, and Kaplan-Meier survival analysis was performed. Logistic regression equation was used to identify prognostic factors of HFrecEF. Results: A total of 310 patients with heart failure were included. There were 91(29.4%) HFrEF patients, 38(12.3%) HFrecEF patients and 181(58.4%) HFpEF patients. Compared with HFrEF patients and HFpEF patients, HFrecEF patients were featured by younger age, more likely to be female, higher systolic blood pressure, diastolic blood pressure and resting heart rate (all P<0.05). Dilated cardiomyopathies were more common, while old myocardial infarctions were less common in HFrecEF (both P<0.05). During a median follow-up of 36.7(18.0, 63.9) months, Kaplan-Meier survival analysis found that HFrecEF patients had the lowest all-cause mortality (Log-rank P=0.047, HFrecEF vs. HFpEF P=0.017, HFrecEF vs. HFrEF P=0.016, and HFpEF vs. HFrEF P=0.782).The cardiovascular mortality ranged from low to high was in HFrecEF patients, HFpEF patients, and HFrEF patients (Log-rank P<0.001, HFrecEF vs. HFpEF P=0.029, HFrecEF vs. HFrEF P<0.001, HFrEF vs. HFpEF P=0.005). Sudden death rate was similar among the three groups (Log-rank P=0.520). Logistic regression analysis showed that left ventricular end-diastolic diameter (LVEDD)≤55 mm (OR=5.922, 95%CI 1.685-20.812, P=0.006), higher diastolic blood pressure (OR=1.058, 95%CI 1.017-1.100, P=0.005), faster resting heart rate (OR=1.042, 95%CI 1.006-1.080, P=0.024), absence of old myocardial infarction (OR=5.343, 95%CI 1.731-16.488, P=0.004) were independent prognostic factors of LVEF recovery after clinical treatment. Conclusions: Patients with HFrecEF are associated with a better prognosis as compared to patients with HFrEF and HFpEF. LVEDD≤55 mm, higher diastolic blood pressure, faster heart rate,and absence of old myocardial infarction are independent prognostic factors of LVEF recovery after clinical treatment.

Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression.

BACKGROUND: Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanisms to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa. METHODS: To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry, and ultra-high pressure liquid chromatography on these samples to quantify the KP enzyme gene, protein, and activity, respectively. RESULTS: We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression, and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA). CONCLUSIONS: Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

NAD Deficiency, Congenital Malformations, and Niacin Supplementation.

BACKGROUND: Congenital malformations can be manifested as combinations of phenotypes that co-occur more often than expected by chance. In many such cases, it has proved difficult to identify a genetic cause. We sought the genetic cause of cardiac, vertebral, and renal defects, among others, in unrelated patients. METHODS: We used genomic sequencing to identify potentially pathogenic gene variants in families in which a person had multiple congenital malformations. We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma. We engineered mouse models with similar variants using the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system. RESULTS: Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21). Another patient carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4). The mutant enzymes had greatly reduced activity in vitro. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan through the kynurenine pathway. The patients had reduced levels of circulating NAD. Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency. In null mice, the prevention of NAD deficiency during gestation averted defects. CONCLUSIONS: Disruption of NAD synthesis caused a deficiency of NAD and congenital malformations in humans and mice. Niacin supplementation during gestation prevented the malformations in mice. (Funded by the National Health and Medical Research Council of Australia and others.).

Epithelial Indoleamine 2,3-Dioxygenase 1 Modulates Aryl Hydrocarbon Receptor and Notch Signaling to Increase Differentiation of Secretory Cells and Alter Mucus-Associated Microbiota.

BACKGROUND & AIMS: Inflammation, injury, and infection up-regulate expression of the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in the intestinal epithelium. We studied the effects of cell-specific IDO1 expression in the epithelium at baseline and during intestinal inflammation in mice. METHODS: We generated transgenic mice that overexpress fluorescence-tagged IDO1 in the intestinal epithelium under control of the villin promoter (IDO1-TG). We generated intestinal epithelial spheroids from mice with full-length Ido1 (controls), disruption of Ido1 (knockout mice), and IDO1-TG and analyzed them for stem cell and differentiation markers by real-time polymerase chain reaction, immunoblotting, and immunofluorescence. Some mice were gavaged with enteropathogenic Escherichia coli (E2348/69) to induce infectious ileitis, and ileum contents were quantified by polymerase chain reaction. Separate sets of mice were given dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid to induce colitis; intestinal tissues were analyzed by histology. We utilized published data sets GSE75214 and GDS2642 of RNA expression data from ilea of healthy individuals undergoing screening colonoscopies (controls) and patients with Crohn's disease. RESULTS: Histologic analysis of small intestine tissues from IDO1-TG mice revealed increases in secretory cells. Enteroids derived from IDO1-TG intestine had increased markers of stem, goblet, Paneth, enteroendocrine, and tuft cells, compared with control enteroids, with a concomitant decrease in markers of absorptive cells. IDO1 interacted non-enzymatically with the aryl hydrocarbon receptor to inhibit activation of NOTCH1. Intestinal mucus layers from IDO1-TG mice were 2-fold thicker than mucus layers from control mice, with increased proportions of Akkermansia muciniphila and Mucispirillum schaedleri. Compared to controls, IDO1-TG mice demonstrated an 85% reduction in ileal bacteria (P = .03) when challenged with enteropathogenic E coli, and were protected from immune infiltration, crypt dropout, and ulcers following administration of dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid. In ilea of Crohn's disease patients, increased expression of IDO1 correlated with increased levels of MUC2, LYZ1, and aryl hydrocarbon receptor, but reduced levels of SLC2A5. CONCLUSIONS: In mice, expression of IDO1 in the intestinal epithelial promotes secretory cell differentiation and mucus production; levels of IDO1 are positively correlated with secretory cell markers in ilea of healthy individuals and Crohn's disease patients. We propose that IDO1 contributes to intestinal homeostasis.

Kynurenine pathway modulation reverses the experimental autoimmune encephalomyelitis mouse disease progression.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system characterized by demyelination, neuroinflammation, and neurodegeneration. Activation of the kynurenine pathway (KP) results from acute and chronic neuroinflammation leading to both immune suppression and neurotoxicity. However, the exact effects of KP metabolites and changes in neurodegenerative diseases over time are not fully understood. Studies, including those in MS models, have reported that short-term KP activation is beneficial through immune tolerance. However, the effects of long-term KP activation are poorly understood. We hypothesized that such chronic activation is responsible for the neurodegeneration in MS, and further, modulating the KP in EAE-induced mice could significantly decrease the EAE disease severity. METHODS: We biochemically altered the KP at different stages of the disease in experimental allergic encephalomyelitis (EAE) mouse model of MS and at two different enzymatic levels of the KP (IDO-1 (indoleamine 2,3 dioxygenase)) and KMO (kynurenine monooxygenase). CNS tissue and blood samples were analyzed longitudinally using GCMS, HPLC, IHC, and RT-PCR. RESULTS: We showed that the KP was steadily upregulated correlating with disease severity and associated with a shift towards increasing concentrations of the KP metabolite quinolinic acid, a neuro- and gliotoxin. KP modulation by inhibition of IDO-1 with 1-methyl tryptophan (1-MT) was dependent on the timing of treatment at various stages of EAE. IDO-1 inhibition at EAE score 2 led to significantly higher numbers of FoxP3 cells (p < 0.001) in the spleen than earlier IDO-1 inhibition (prophylactic 1-MT treatment group (p < 0.001)), 1-MT treatment after EAE induction (EAE score 0; p < 0.001), and 1-MT treatment at EAE score of 1 (p < 0.05). Significant improvement of disease severity was observed in EAE mice treated with 1-MT at EAE score 2 compared to the untreated group (p < 0.05). KP modulation by KMO inhibition with Ro 61-8048 led to significantly greater numbers of Foxp3 cells (p < 0.05) in Ro 61-8048 treated mice and even more significant amelioration of EAE disease compared to the 1-MT treatment groups. CONCLUSIONS: These results provide a new mechanistic link between neuroinflammation and neurodegeneration and point to KP modulation at the KMO level to preserve immune tolerance and limit neurodegeneration in EAE. They provide the foundation for new clinical trials for MS.

Inflammation and kynurenine pathway dysregulation in post-partum women with severe and suicidal depression.

Depression during pregnancy and the post-partum is common, with severe cases resulting in suicidal behavior. Despite the urgent and unmet medical need, the biological underpinnings of peri-partum depression remain unclear. It has been suggested that it is triggered by dynamic changes of the immune system during pregnancy and at delivery. Therefore, we investigated whether a pro-inflammatory status in plasma, together with changes in the kynurenine pathway activity, is associated with the development of severe depression and suicidal behavior in the post-partum. Our cross-sectional study targets a unique, understudied population in which the pronounced severity of symptoms required hospitalization. We analyzed plasma IL-1ß, IL-2, IL-6, IL-8, TNF-α, tryptophan, serotonin, kynurenine, nicotinamide, quinolinic- and kynurenic acids in post-partum women diagnosed with peripartum onset depression (PPD) and healthy controls (n = 165). We assessed depression severity using the Edinburgh Postnatal Depression Scale and suicidality using the Columbia-Suicide Severity Rating Scale. We found that increased plasma IL-6 and IL-8 and reductions of serotonin, IL-2 and quinolinic acid were associated with the severity of depressive symptoms and increased the risk for PPD. Moreover, women with lower serotonin levels were at an increased risk for suicidal behavior, even when adjusting for depression severity, psychosocial factors, age BMI, and medication. Our results indicate that severe depression in the post-partum involves dysregulation of the immune response and the kynurenine pathway, with a concomitant reduction in serotonin levels. We propose that inflammatory cytokines and the kynurenine pathway are potential treatment targets in PPD, opening up the possibility of novel therapeutic strategies targeting the peripartum.

Plasma neurofilament light chain and amyloid-ß are associated with the kynurenine pathway metabolites in preclinical Alzheimer's disease.

BACKGROUND: Blood markers indicative of neurodegeneration (neurofilament light chain; NFL), Alzheimer's disease amyloid pathology (amyloid-ß; Aß), and neuroinflammation (kynurenine pathway; KP metabolites) have been investigated independently in neurodegenerative diseases. However, the association of these markers of neurodegeneration and AD pathology with neuroinflammation has not been investigated previously. Therefore, the current study examined whether NFL and Aß correlate with KP metabolites in elderly individuals to provide insight on the association between blood indicators of neurodegeneration and neuroinflammation. METHODS: Correlations between KP metabolites, measured using liquid chromatography and gas chromatography coupled with mass spectrometry, and plasma NFL and Aß concentrations, measured using single molecule array (Simoa) assays, were investigated in elderly individuals aged 65-90 years, with normal global cognition (Mini-Mental State Examination Score ≥ 26) from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort. RESULTS: A positive correlation between NFL and the kynurenine to tryptophan ratio (K/T) reflecting indoleamine 2,3-dioxygenase activity was observed (r = .451, p < .0001). Positive correlations were also observed between NFL and kynurenine (r = .364, p < .0005), kynurenic acid (r = .384, p < .0001), 3-hydroxykynurenine (r = .246, p = .014), anthranilic acid (r = .311, p = .002), and quinolinic acid (r = .296, p = .003). Further, significant associations were observed between plasma Aß40 and the K/T (r = .375, p < .0005), kynurenine (r = .374, p < .0005), kynurenic acid (r = .352, p < .0005), anthranilic acid (r = .381, p < .0005), and quinolinic acid (r = .352, p < .0005). Significant associations were also observed between plasma Aß42 and the K/T ratio (r = .215, p = .034), kynurenic acid (r = .214, p = .035), anthranilic acid (r = .278, p = .006), and quinolinic acid (r = .224, p = .027) in the cohort. On stratifying participants based on their neocortical Aß load (NAL) status, NFL correlated with KP metabolites irrespective of NAL status; however, associations between plasma Aß and KP metabolites were only pronounced in individuals with high NAL while associations in individuals with low NAL were nearly absent. CONCLUSIONS: The current study shows that KP metabolite changes are associated with biomarker evidence of neurodegeneration. Additionally, the association between KP metabolites and plasma Aß seems to be NAL status dependent. Finally, the current study suggests that an association between neurodegeneration and neuroinflammation manifests in the periphery, suggesting that preventing cytoskeleton cytotoxicity by KP metabolites may have therapeutic potential.

[Contemporary epidemiology and treatment of hospitalized heart failure patients in real clinical practice in China].

Objective: To observe the etiology, comorbidities, clinical features and treatment patterns of hospitalized patients with heart failure (HF) in China. Methods: Data were collected prospectively on hospitalized patients with HF who were enrolled in China Heart Failure Center Registry Study from 169 participating hospitals from January 2017 to August 2018. In this cross-sectional study, patients were stratified by left ventricular ejection fraction (LVEF) category: heart failure with reduced ejection fraction (HFrEF, LVEF<40%); heart failure with mid-ranged ejection fraction (HFmrEF, 40%≤LVEF<50%) and heart failure with preserved ejection fraction (HFpEF, LVEF≥50%). The clinical data were collected, including demographic information, diagnosis, signs, electrocardiogram, echocardiography, laboratory tests, and treatment. Results: A total of 31 356 hospitalized patients with HF were included, 19 072 (60.8%) were males and the average age was (67.9±13.6) years old. The common causes of HF were hypertension (57.2%), coronary heart disease (54.6%), dilated cardiomyopathy (14.7%), valvular heart disease (9.2%). The common complications were atrial fibrillation/atrial flutter (34.1%), diabetes (29.2%), and anemia (26.7%). 32.8% of patients had a history of hospitalization for HF within the previous 12 months. There were 11 034 (35.2%) patients with HFrEF, 6 825 (21.8%) patients with HFmrEF and 13 497 (43.0%) patients with HFpEF. Compared with patients with HFpEF, patients with HFrEF had a lower systolic blood pressure ((124.7±21.1)mmHg(1 mmHg=0.133 kPa) vs. (134.9±22.9)mmHg), faster heart rate ((85±19) beats/minutes vs. (81±19)beats/minutes), and higher percentage of New York Heart Association (NYHA) class Ⅳ, smoking, alcohol, left bundle branch block, and QRS time≥130 ms, and higher levels of blood uric acid, BNP, and NT-proBNP (all P<0.05). Compared with patients with HFmrEF and HFrEF, patients with HFpEF were older, more women, and higher comorbidity burden including hypertension, atrial fibrillation/atrial flutter, anemia and chronic obstructive pulmonary disease (all P<0.05). HFmrEF took a mid-position between HFrEF and HFpEF in age, gender, heart rate, systolic blood pressure, hypertension, atrial fibrillation/atrial flutter, anemia, and chronic obstructive pulmonary disease (all P<0.05). Patients with HFmrEF had the highest proportion of coronary heart disease, myocardial infarction and percutaneous coronary intervention (all P<0.05). During hospitalization, loop diuretics were used in 90.2% of patients, and intravenous inotropics were used in 20.4% of patients. The use of ACEI/ARB/ARNI, ß blockers and aldosterone receptor antagonists at discharge were 71.8%, 79.1% and 83.6% in HFrEF and 69.9%, 75.5% and 72.4% in HFmrEF, respectively. The use of digoxin at discharge was 25.3% (HFrEF 36.7%, HFmrEF 23.1%, HFpEF 17.0%). The rates of cardiac resynchronization therapy and implantable cardioverter defibrillator in HFrEF were 2.7% and 2.1%. Conclusions: Among the hospitalized patients with HF in China, coronary heart disease and hypertension are the mostly prevalent causes. HFpEF accounts for a large proportion of hospitalized patients with HF. HFrEF, HFmrEF and HFpEF have different etiology and clinical features. In real-world, there are still large gaps in the effective application of the guideline recommended therapies to HF patients, especially the non-pharmacological therapy option, which needs to be improved further in China.

Soluble LILRA3 promotes neurite outgrowth and synapses formation through a high-affinity interaction with Nogo 66.

Inhibitory proteins, particularly Nogo 66, a highly conserved 66-amino-acid loop of Nogo A (an isoform of RTN4), play key roles in limiting the intrinsic capacity of the central nervous system (CNS) to regenerate after injury. Ligation of surface Nogo receptors (NgRs) and/or leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue the paired immunoglobulin-like receptor B (PIRB) by Nogo 66 transduces inhibitory signals that potently inhibit neurite outgrowth. Here, we show that soluble leukocyte immunoglobulin-like receptor A3 (LILRA3) is a high-affinity receptor for Nogo 66, suggesting that LILRA3 might be a competitive antagonist to these cell surface inhibitory receptors. Consistent with this, LILRA3 significantly reversed Nogo-66-mediated inhibition of neurite outgrowth and promoted synapse formation in primary cortical neurons through regulation of the ERK/MEK pathway. LILRA3 represents a new antagonist to Nogo-66-mediated inhibition of neurite outgrowth in the CNS, a function distinct from its immune-regulatory role in leukocytes. This report is also the first to demonstrate that a member of LILR family normally not expressed in rodents exerts functions on mouse neurons through the highly homologous Nogo 66 ligand.

[The expressions of VEGF and VEGFR signaling pathway in the bone marrow mononuclear cells with chronic mountain sickness].

Objective: This study was aimed at investigating the levels and relationships of vascular endothelial growth factor (VEGF) and its receptor(VEGFR) in the bone marrow mononuclear cells (MNC) of chronic mountain sickness (CMS). Methods: A total of 34 patients with CMS and 30 controls residing at altitudes of 3 000-4 500 m were recruited for this study. The levels of VEGF, VEGFR1 and VEGFR2 in bone marrow MNC were detected by flow cytometry technique and RT-qPCR. Results: The percentage of VEGFR2 positive cells in the bone marrow MNC of CMS were higher than that of the controls[20.7% (8.1%, 67.6%) vs 8.1% (2.2%, 14.9%), P<0.05], but that of VEGFR1-positive and VEGF-positive were similar in CMS and controls. The mRNA levels of VEGFR2 were higher in the bone marrow MNC of CMS than in the controls[1.7(1.0, 5.1) vs 1.0(0.4, 2.7), P<0.05], while VEGF and VEGFR1 mRNA levels were similar between the two groups. The percentage of VEGFR2 positive cells in CMS were significantly correlated with hemoglobin (r=0.453, P=0.007) and the percentage of VEGF-positive cells (r=0.373, P=0.030). Conclusions: Bone marrow MNC of CMS may show enhanced activity of the VEGF-VEGFR2 pathway, and it appears to be involved in the pathogenesis of CMS.

[Myocardial amyloid deposition in patients aged over 85 years with heart failure and preserved ejection fraction].

Objective: To determine the frequency and extent of left ventricular amyloid deposition in patients aged over 85 years with heart failure and preserved ejection fraction (HFpEF). Methods: A total of 43 patients aged 85 to 100 years old were enrolled in this study based on the autopsy database of Beijing Hospital from February 1, 2003 to October 31, 2016. The frequency and extent of left ventricular amyloid deposition and myocardial fibrosis were determined in left ventricular specimens from patients with antemortem diagnosis of HFpEF without clinically apparent amyloid (n=28) and from control subjects (n=15) post Congo red staining and Masson's trichrome staining. Kappa test was used to evaluate the consistency of the myocardial amyloidosis and fibrosis. Results: The heart weight of the patients in HFpEF group and in control group were similar((452.7±107.7)g vs. (415.0±70.8)g, t=-1.218, P=0.23)). Positive Congo-red staining was found in 24 examples (24/28) in HFpEF group and 5 examples (5/15) in the control group; severe amyloid deposition was found in 7 examples (7/28) in HFpEF group, but not in the control group. Amyloid deposition was more severe in HFpEF group than in control group (χ(2)=12.205, P<0.01). Masson's trichrome staining evidenced moderate to severe fibrosis in 19 cases (19/28) in HFpEF group and 8 cases (8/15) in control group (χ(2)=1.019, P=0.35). A consistent evaluation of the degree of myocardial fibrosis and the degree of myocardial amyloid deposition in all selected participants was performed and results showed that these two parameters were not consistent (Kappa value=0.2, P=0.820). Conclusion: Amyloid deposition is common in the elderly patients with heart failure and preserved ejection fraction, suggesting that myocardial amyloidosis may be related to the development of HFpEF. There is no significant correlation between myocardial amyloidosis and myocardial fibrosis in this cohort.

Human regulatory macrophages are potent in suppression of the xenoimmune response via indoleamine-2,3-dioxygenase-involved mechanism(s).

BACKGROUND: For xenotransplantation to truly succeed, we must develop immunomodulatory strategies to suppress the xenoimmune response but by minimizing immunosuppression over the long term. Regulatory macrophages (Mreg) have been shown to suppress polyclonal T-cell proliferation in vitro and prolong allograft survival in vivo. However, the question of whether they are capable of suppressing xenoimmune responses remains unknown. This study assessed the potential of human Mreg to be used as an effective immunomodulatory method in xenotransplantation. METHODS: CD14+ monocytes selected from human peripheral blood mononuclear cells (PBMC) were cultured with macrophage colony-stimulating factor (M-CSF) for 7 days with IFN-γ added at day 6 for Mreg induction. Mreg phenotyping was performed by flow cytometric analysis, and the in vitro suppressive function was assessed by mixed lymphocyte reaction (MLR) using irradiated pig PBMC as the xenogeneic stimulator cells, human PBMC as responder cells, and autologous Mreg as suppressor cells. To assess mRNA expression of Mreg functional molecules indoleamine-2,3-dioxygenase (IDO), IL-10, inducible nitric oxide synthase (iNOS) and TGF-ß were measured by real-time PCR. Supernatants were collected from the MLR cultures for IDO activity assay by high-performance liquid chromatography (HPLC). The effects of the IDO inhibitor 1-D/L-methyl-tryptophan (1-MT), iNOS inhibitor NG -monomethyl-l-arginine (L-NMMA), and anti-IFN-γ or anti-TGF-ß monoclonal antibody (mAb) treatment on Mreg suppressive capacity were tested from the supernatants of the MLR assays. RESULTS: We demonstrated that induced Mreg with a phenotype of CD14low CD16-/low CD80low CD83-/low CD86+/hi HLA-DR+/hi were capable of suppressing proliferating human PBMC, CD4+, and CD8+ T cells, even at a higher responder:Mreg ratio of 32:1 in a pig-human xenogeneic MLR. The strong suppressive potency of Mreg was further correlated with their upregulated IDO expression and activity. The IDO upregulation of Mreg was associated with an increased production of IFN-γ, an IDO stimulator, by xenoreactive responder cells in the xenogeneic MLR. While no effect on Mreg suppressive potency was detected by addition of the iNOS inhibitor L-NMMA or anti-TGF-ß mAb into the MLR assays, inhibition of IDO activity by neutralizing IFN-γ or by IDO inhibitor 1-MT substantially impaired the capacity of Mreg to suppress the xenogeneic response, indicating the importance of upregulated IDO activity in Mreg-mediated suppression of the xenogeneic response in vitro. CONCLUSION: This study demonstrates that human Mreg are capable of suppressing the xenoimmune response in vitro via IDO-involved mechanism(s), suggesting their potential role as an effective immunomodulatory tool in xenotransplantation.

[Pathological characteristics of the heart and coronary artery from elderly heart failure patients with preserved ejection fraction and coronary artery disease].

Objective: To analyze the pathological feathers of the heart in elderly (60-99 years old) heart failure patients with preserved ejection fraction (HFpEF) and coronary artery disease (CAD) and to explore the misdiagnosis and missed diagnosis rates. Method: This retrospective study included 154 HFpEF (left ventricular ejection fraction (LVEF)≥50%) cases and 49 heart failure with reduced ejection fraction (HFrEF) (LVEF≤40%) cases aged 60-99 years old out of 1 485 consecutive autopsy cases. Pathological changes of the heart and coronary artery were compared between patients with HFpEF and HFrEF. The misdiagnosis and missed diagnosis rates of HFpEF were analyzed based on pathological examination. Results: Patients with HFpEF were older than those with HFrEF ((85.7±7.4) vs. (82.9±7.8) years old, P=0.017). Among all the cases, CAD was diagnosed in 105 (68.2%) HFpEF patients and 38 (77.6%) HFrEF patients. Compared with patients with HFrEF, HFpEF patients displayed less acute myocardial infarction (12.3%(19/154) vs. 59.2%(29/49), P<0.01) and more chronic myocardial ischemia (18.2%(28/154) vs. 6.1%(3/49), P=0.041). 51.9% (80/154) HFpEF and 71.4% (35/49) HFrEF patients (P=0.017) displayed >50% left anterior descending artery stenosis. Prevalence of >75% coronary arterial stenosis (51% (25/49) vs. 20.1%(31/154), P<0.001) and more than one vessel lesions (55.1%(27/49) vs. 33.8%(52/154), P=0.008) were significantly higher in HFrEF patients than in HFpEF patients. The misdiagnosis rate of CAD in HFpEF was 63.3% (31/49). Among HFpEF, the missed diagnosis rate of acute myocardial infarction was 57.9% (11/19) and the missed diagnosis rate of old myocardial infarction was 57.7% (45/78). Conclusions: CAD and chronic myocardial ischemia are common in elderly patients with HFpEF. Chronic myocardial ischemia may play an important role in the development of HFpEF of elderly CAD patients. Among HFpEF patients, the misdiagnosis rate of CAD and missed diagnosis rate of myocardial infarction are high, so the accurate evaluation of myocardial ischemia status is of great importance.

[Pathological features at autopsy in elderly patients with acute myocardial infarction].

Objective: To analyze the cardiac pathological features of elderly coronary artery disease (CAD) patients (60 years and over) and evaluate the pathological features at autopsy and risk factors of patients with acute myocardial infarction (AMI). Methods: Data from 471 elderly patients (aged from 60 to 100 years old) with CAD confirmed by autopsy hospitalized in our hospital from April 1969 to October 2013 were retrospectively reviewed. Patients were divided into 2 groups: AMI group(n=128) with AMI as the primary cause of death and the rest served as control group(n=343). The pathological features of coronary lesion and related risk factors of AMI were analyzed. Results: In patients aged 60 and over with CAD, 48.8%(230/471) had severe coronary stenosis, 18.7%(88/471) had three-vessel disease, 71.8% cases (338/471) had left anterior descending artery(LAD)grade Ⅲ and over stenosis, 29.9% (141/471) had LAD grade Ⅳ stenosis, 25.9%(122/471) had left main coronary artery(LM) grade Ⅲ and over stenosis, 9.6%(45/471) had LM grade Ⅳ stenosis, 27.1%(128/471) had AMI. The first AMI accounts for 39.1%(50/128), and 60.9%(78/128) had both AMI and old MI. Compared with the control group, AMI group were younger ((77.1±11.6) years vs. (83.2±9.1) years, P<0.01), had more severe coronary artery stenosis lesion (77.3%(99/128) vs. 38.2%(131/343), P<0.01), higher coronary index which reflects the overall arteriosclerosis (9.9±2.8 vs. 8.0±2.5, P<0.01), more three-vessel disease (30.3%(43/128) vs. 13.7%(45/343), P<0.01), heavier heart weight ((447.8±90.6)g vs. (426.6±99.1)g, P<0.05), higher prevlence of pulmonary congestion or edema (57.8%(74/128) vs. 39.9%(137/343), P<0.01). Twenty-three cardiac ruptures (23/128, 18.0%) were observed in AMI group. Logistic regression analysis showed that grade Ⅳ LAD stenosis (OR=3.55, 95%CI 2.05-6.17, P<0.01), three-vessel disease(OR=2.47, 95%CI 1.30-4.67, P<0.01) were the independent risk factors of AMI in elderly patients with CAD. Conclusions: Severe coronary stenosis is common in CAD patients aged 60 and over. Patients aged 60 and over with AMI have more severe coronary artery stenosis lesion and heavier heart weight. Cardiac rupture is not uncommon in elderly patients with AMI. Severe LAD stenosis and three-vessel disease are the independent risk factors of AMI in the elderly.