Evaluation among trace elements, clinical parameters and type 1 diabetes according to sex: A new sight of auxiliary prediction in negative insulin auto-antibodies population.

BACKGROUND: Type 1 diabetes (T1D) exhibited sex-specific metabolic status including oxidative stress with dynamic change of trace elements, which emphasized the importance of the evaluation of trace elements according to sex. Besides, the most significant characteristic, insulin auto-antibodies, could not be found in all T1D patients, which needed the auxiliary prediction of clinical parameters. And it would benefit the early detection and treatment if some high-risk groups of T1D could predict and prevent the occurrence of disease through common clinical parameters. Hence, there was an urgent need to construct more effective and scientific statistical prediction models to serve clinic better. This study aimed to evaluate the sex-specific levels of trace elements and the relationship between trace elements and clinical parameters in T1D, and construct sex-specific auxiliary prediction model combined with trace elements and clinical parameters. METHODS: A total of 105 T1D patients with negative insulin auto-antibodies and 105 age/sex-matched healthy individuals were enrolled in First Hospital of Jilin University. Inductively Coupled Plasma Mass Spectrometry was performed for the measurement of calcium (Ca), magnesium (Mg), zinc (Zn), copper (Cu), iron (Fe), selenium (Se) in the serum, and the data of clinical parameters were received from medical record system. The lambda-mu-sigma method was used to evaluate the relationship between abnormal clinical parameters and trace elements. Training set and validation set were divided for the construction of predictable models in males and females: clinical parameters model, trace element model and the combined model (clinical parameters and trace elements). Goodness fit test, decision curve analysis and other related statistical methods were used to perform data analysis. RESULTS: Lower levels of Mg, Ca, Fe in the serum were found in T1D population in females compared with healthy population, while levels of Fe, Zn and Cu of serum in T1D individuals were higher than those of healthy population in males. Levels of serum Mg, Fe and Cu in T1D group were found with significant sex difference for (P < 0.05), and the levels of Fe and Cu in serum of males were higher than those of females, level of serum Mg in males was lower than those of females. Levels of serum Mg and Zn showed fluctuation trend with increased numbers of abnormal clinical parameters (NACP) in males. Serum Zn in females showed consistent elevated trend with NACP; serum Se increased first and then decreased with NACP in males and females. The auxiliary prediction model (Triglyceride, Total protein, serum Mg) was found with the highest predicted efficiency in males (AUC=0.993), while the model in females (Apolipoprotein A, Creatinine, Fe, Se, Zn/Cu ratio) showed the best predicted efficiency (AUC=0.951). The models had passed the verification in validation set, and Chi-square goodness-of-fit test, DCA results both confirmed their satisfactory clinical applicability. CONCLUSION: Sex-specific difference were found in serum Mg, Fe and Cu in T1D. The combination of triglyceride, total protein and serum Mg for males, and apolipoprotein A, creatinine, Fe, Se, Zn/Cu ratio for females could effectively predict T1D in patients with negative anti-bodies, which would provide alarm for the population with high-risk of T1D and serve the T1D prediction in patients with negative anti-bodies.

Towards early risk biomarkers: serum metabolic signature in childhood predicts cardio-metabolic risk in adulthood.

BACKGROUND: Cardiovascular diseases may originate in childhood. Biomarkers identifying individuals with increased risk for disease are needed to support early detection and to optimise prevention strategies. METHODS: In this prospective study, by applying a machine learning to high throughput NMR-based metabolomics data, we identified circulating childhood metabolic predictors of adult cardiovascular disease risk (MetS score) in a cohort of 396 females, followed from childhood (mean age 11·2 years) to early adulthood (mean age 18·1 years). The results obtained from the discovery cohort were validated in a large longitudinal birth cohort of females and males followed from puberty to adulthood (n = 2664) and in four cross-sectional data sets (n = 6341). FINDINGS: The identified childhood metabolic signature included three circulating biomarkers, glycoprotein acetyls (GlycA), large high-density lipoprotein phospholipids (L-HDL-PL), and the ratio of apolipoprotein B to apolipoprotein A-1 (ApoB/ApoA) that were associated with increased cardio-metabolic risk in early adulthood (AUC = 0·641‒0·802, all p<0·01). These associations were confirmed in all validation cohorts with similar effect estimates both in females (AUC = 0·667‒0·905, all p<0·01) and males (AUC = 0·734‒0·889, all p<0·01) as well as in elderly patients with and without type 2 diabetes (AUC = 0·517‒0·700, all p<0·01). We subsequently applied random intercept cross-lagged panel model analysis, which suggested bidirectional causal relationship between metabolic biomarkers and cardio-metabolic risk score from childhood to early adulthood. INTERPRETATION: These results provide evidence for the utility of a circulating metabolomics panel to identify children and adolescents at risk for future cardiovascular disease, to whom preventive measures and follow-up could be indicated. FUNDING: This study was financially supported by the Academy of Finland, Ministry of Education of Finland and University of Jyv€askyl€a, the National Nature Science Foundation of China (Grant 31571219), the 111 Project (B17029), the Shanghai Jiao Tong University Zhiyuan Foundation (Grant CP2014013), China Postdoc Scholarship Council (201806230001), the Food and Health Bureau of Hong Kong SAR's Health and Medical Research Fund (HMRF grants 15162161 and 07181036) and the CUHK Direct Grants for Research (2016¢033 and 2018¢034), and a postdoctoral fellowship from K. Carole Ellison (to T.W.). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. NFBC1966 received financial support from University of Oulu Grant no. 24000692, Oulu University Hospital Grant no. 24301140, ERDF European Regional Development Fund Grant no. 539/2010 A31592. This work was supported by European Union's Horizon 2020 research and innovation programme LongITools 874739.

Dyslipidemia Is Related to Mortality in Critical Patients With Coronavirus Disease 2019: A Retrospective Study.

Background: It has been reported that dyslipidemia is related to coronavirus-related diseases. Critical patients with coronavirus disease 2019 (COVID-19) who suffered from multiple organ dysfunctions were treated in the intensive care unit (ICU) in Wuhan, China. Whether the lipids profile was associated with the prognosis of COVID-19 in critical patients remained unclear. Methods: A retrospective study was performed in critical patients (N=48) with coronavirus disease 2019 in Leishenshan hospital between February and April 2020 in Wuhan. The parameters including lipid profiles, liver function, and renal function were collected on admission day, 2-3days after the admission, and the day before the achievement of clinical outcome. Results: Albumin value and creatine kinase (ck) value were statistically decreased at 2-3 days after admission compared with those on admission day (P<0.05). Low density lipoprotein (LDL-c), high density lipoprotein (HDL-c), apolipoprotein A (ApoA), and apolipoprotein A (Apo B) levels were statistically decreased after admission (P<0.05). Logistic regression showed that HDL-c level both on admission day and the day before the achievement of clinical outcome were negatively associated with mortality in critical patients with COVID-19. Total cholesterol (TC) level at 2-3days after admission was related to mortality in critical patients with COVID-19. Conclusions: There were lipid metabolic disorders in the critical patients with COVID-19. Lower levels of HDL-c and TC were related to the progression of critical COVID-19.

Novel proteins associated with chronic intermittent hypoxia and obstructive sleep apnea: From rat model to clinical evidence.

OBJECTIVE: To screen for obstructive sleep apnea (OSA) biomarkers, isobaric tags for relative and absolute quantitation (iTRAQ)-labeled quantitative proteomics assay was used to identify differentially expressed proteins (DEPs) during chronic intermittent hypoxia (CIH). METHOD: The iTRAQ technique was applied to compare DEPs in the serum of a CIH rat model and control group. Biological analysis of DEPs was performed using Gene Ontology and Kyoto Encyclopedia to explore related biological functions and signaling pathways. Enzyme-linked immunosorbent assay (ELISA) was performed to validate their expression in sera from patients with OSA and CIH rats. RESULTS: Twenty-three DEPs (fold change ≥1.2 or ≤0.833, p<0.05) were identified, and two DEPs (unique peptides>3 and higher coverage) were further verified by ELISA in the CIH rat model and OSA subject: apolipoprotein A-IV (APOA4, p<0.05) and Tubulin alpha-1A chain (TUBA1A, p<0.05). Both groups showed significant differences in the expression levels of DEPs between the CIH and control groups and the severe OSA and non-OSA groups. APOA4 was found to be upregulated and TUBA1A downregulated in both the sera from OSA patients and CIH rats, on comparing proteomics results with clinical results. There were two pathways that involved three DEPs, the mitogen-activated protein kinase (MAPK) signaling pathway (p<0.05) and cytokine-cytokine receptor interaction (p<0.05). CONCLUSION: APOA4 and TUBA1A may be potential novel biomarkers for CIH and OSA, and may play an important role in the development of OSA complications.

Label-free electrochemical homogeneous detection of the depression marker human apolipoprotein A4 based on proximity hybridization triggered rolling circle amplification.

In this paper, we developed a label-free homogeneous electrochemical sensor for detection of apolipoprotein A4 based on proximity hybridization triggered rolling circle amplification induced G-quadruplex formation. The presence of apolipoprotein A4 promoted the formation of a proximate complex via the proximity hybridization of the aptamer DNA strands, which unfolded the molecular beacon, the stem part of molecular beacon as a primer to initiate the RCA process. Thus, with the electrochemical indicator hemin selectively intercalated into the multiple G-quadruplexes, a significant electrochemical signal drop is observed, which is dependent on the concentration of the target apolipoprotein A4. Thus, using this "signal-off" mode, label-free homogeneous electrochemical strategy for sensitive apolipoprotein A4 assay with a wide range from 1 pg mL-1 to 100 ng mL-1, with a low detection limit of 0.51 pg mL-1. And it rendered satisfactory analytical performance for the determination of apolipoprotein A4 in serum samples. Furthermore, this method also exhibits additional advantages of simplicity and low cost, since both expensive labeling and sophisticated probe immobilization processes are avoided. The satisfactory results indicated that the proposed sensor had promising potential in the clinical diagnosis of depression.

Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112).

BACKGROUND: Hepatocyte growth factor (HGF) is an endogenously induced bioactive molecule that has strong anti-apoptotic and tissue repair activities. In this research, we identified APOA4 as a novel pharmacodynamic (PD) marker of the recombinant human HGF (rh-HGF), E3112. METHODS: rh-HGF was administered to mice, and their livers were investigated for the PD marker. Candidates were identified from soluble proteins and validated by using human hepatocytes in vitro and an animal disease model in vivo, in which its c-Met dependency was also ensured. RESULTS: Among the genes induced or highly enhanced after rh-HGF exposure in vivo, a soluble apolipoprotein, Apoa4, was found to be induced by rh-HGF in the murine liver. By using primary cultured human hepatocytes, the significant induction of human APOA4 was observed at the mRNA and protein levels, and it was inhibited in the presence of a c-Met inhibitor. Although mice constitutively expressed Apoa4 mRNA in the small intestine and the liver, the liver was the primary organ affected by administered rh-HGF to strongly induce APOA4 in a dose- and c-Met-dependent manner. Serum APOA4 levels were increased after rh-HGF administration, not only in normal mice but also in anti-Fas-induced murine acute liver failure (ALF), which confirmed the pharmacodynamic nature of APOA4. CONCLUSIONS: APOA4 was identified as a soluble PD marker of rh-HGF with c-Met dependency. It should be worthwhile to clinically validate its utility through clinical trials with healthy subjects and ALF patients.

Changes in serum levels of Apo AIV in patients with newly diagnosed hyperthyroidism and hypothyroidism: a preliminary study.

OBJECTIVES: Apolipoprotein AIV has a role in chylomicrons and lipid secretion and catabolism. Also, Apo-AIV plays a role in the regulation of appetite and satiety. Previous studies on rats have shown that hyperthyroidism and hypothyroidism are associated with significant changes in Apo-AIV serum levels. There has been no research on serum Apo-AIV changes in hyper and hypothyroidism in humans. METHODS: This case-control study was performed on new patients with hyper and hypothyroidism. Eighteen patients with hyperthyroidism and 18 patients with hypothyroidism enrolled in the study. After 12 weeks treatment blood samples were recruited. If euthyroidism was achieved, serum Apo-AIV level was measured. Eighteen euthyroid healthy individuals without thyroid disease were chosen as the control group from general population. RESULTS: Serum levels of Apo-AIV before treatment in hypothyroidism, hyperthyroidism and in the control group were 85.61, 110.66 and 33.51 mg/dL respectively (p<0.001), which was significantly higher in hyperthyroid patients than hypothyroidism and control group. In patients with hyperthyroidism there was a significant decrease in serum levels of Apo-AIV after treatment (p=0.044). However in hypothyroidism a non-significant elevation in serum levels of Apo-AIV was observed (p=0.403). Furthermore, serum levels of Apo-AIV after treatment were significantly higher in both hyperthyroidism and hypothyroidism in comparison to control group (p<0.001). CONCLUSIONS: The results of this study for the first time showed that the serum level of Apo-AIV is increased in patients with hyperthyroidism and is decreased in patients with hypothyroidism, and after treatment, there was a significant difference with the control group.

Depression Augments Plasma APOA4 without Changes of Plasma Lipids and Glucose in Female Adolescents Carrying G Allele of APOA4 rs5104.

The association of apolipoprotein AIV (APOA4) with depression or plasma levels of lipids and glucose has been inconsistently reported. However, interplays between APOA4 and depression on the levels have not been explored yet. The present study aimed to investigate plasma levels of APOA4, lipids, and glucose in adolescents with different genotypes of APOA4 rs5104 and with or without depression. Depressive symptoms were assessed in 631 adolescents by Beck Depression Inventory (BDI). A total score of 14 was defined as the cutoff point for depression. Plasma levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glucose, and insulin were measured by routine methods, and APOA4 by enzyme-linked immunosorbent assays. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism analyses and verified by DNA sequencing. Female adolescents had higher prevalence of depression than male subjects only in G allele carriers (p = 0.015), but not in AA homozygotes. Risk factors of depression and predictors of depression severity were different between G allele carriers and AA homozygotes. Lower levels of glucose (p = 0.003) were observed in male G allele carriers than those in male AA homozygotes and increased TG levels (p = 0.008) in female G allele carriers when compared with those in female AA homozygotes. When both APOA4 rs5104 and depression were taken into account, subjects with depression had higher levels of plasma APOA4 than adolescents without depression only in female G allele carriers (p = 0.043), but no significant changes of plasma lipids and glucose. Depression augments plasma APOA4 levels without changes of plasma lipids and glucose in female adolescents carrying G allele of APOA4 rs5104. These results may provide a novel explanation for the inconsistent relationship between depression, APOA4, and plasma levels of lipids and glucose in the literature.

Serum lipid profiles and risk of colorectal cancer: a prospective cohort study in the UK Biobank.

BACKGROUND: It remains unclear whether serum lipids influence colorectal cancer (CRC) risk. METHODS: We conducted a prospective cohort study of 380,087 adults aged 40-69 years in the UK Biobank. Serum high-density cholesterol, low-density cholesterol, total cholesterol, triglycerides, and apolipoprotein A and B were measured. We used Cox proportional hazard models to estimate the multivariable hazard ratios (HRs) of CRC according to one standard deviation (SD) increment in serum lipids. We conducted subgroup analysis by tumour anatomical subsites. RESULTS: During a median of 10.3 years of follow-up, we documented 2667 incident CRC cases. None of the lipid biomarkers was associated with the risk of CRC after adjusting for potential confounding factors, including body mass index and waist circumference. When assessed by cancer subsites, serum triglycerides was associated with an increased risk of cancer in the caecum and transverse colon, with the HR of 1.12 (95% CI, 1.00-1.25) and 1.29 (95% CI, 1.09-1.53), respectively; and apolipoprotein A was associated with a lower risk of hepatic flexure cancer (HR, 0.73, 95% CI, 0.56-0.96). CONCLUSIONS: Serum lipid profiles were not associated with colorectal cancer risk after adjusting for obesity indicators. The potential subsite-specific effects of triglycerides and apolipoprotein A require further confirmation.

Enrichment of apolipoprotein A-IV and apolipoprotein D in the HDL proteome is associated with HDL functions in diabetic kidney disease without dialysis.

BACKGROUND AND AIMS: Diabetic kidney disease (DKD) is associated with lipid derangements that worsen kidney function and enhance cardiovascular (CVD) risk. The management of dyslipidemia, hypertension and other traditional risk factors does not completely prevent CVD complications, bringing up the participation of nontraditional risk factors such as advanced glycation end products (AGEs), carbamoylation and changes in the HDL proteome and functionality. The HDL composition, proteome, chemical modification and functionality were analyzed in nondialysis subjects with DKD categorized according to the estimated glomerular filtration rate (eGFR) and urinary albumin excretion rate (AER). METHODS: Individuals with DKD were divided into eGFR> 60 mL/min/1.73 m2 plus AER stages A1 and A2 (n = 10) and eGFR< 60 plus A3 (n = 25) and matched by age with control subjects (eGFR> 60; n = 8). RESULTS: Targeted proteomic analyses quantified 28 proteins associated with HDL in all groups, although only 2 were more highly expressed in the eGFR< 60 + A3 group than in the controls: apolipoprotein D (apoD) and apoA-IV. HDL from the eGFR< 60 + A3 group presented higher levels of total AGEs (20%), pentosidine (6.3%) and carbamoylation (4.2 x) and a reduced ability to remove 14C-cholesterol from macrophages (33%) in comparison to HDL from controls. The antioxidant role of HDL (lag time for LDL oxidation) was similar among groups, but HDL from the eGFR< 60 + A3 group presented a greater ability to inhibit the secretion of IL-6 and TNF-alpha (95%) in LPS-elicited macrophages in comparison to the control group. CONCLUSION: The increase in apoD and apoA-IV could contribute to counteracting the HDL chemical modification by AGEs and carbamoylation, which contributes to HDL loss of function in well-established DKD.

Increased risk of metabolic dysfunction in children conceived by assisted reproductive technology.

AIMS/HYPOTHESIS: Assisted reproductive technology (ART) is the most widely used treatment for infertility and has resulted in millions of births worldwide. The safety of the offspring has been of the utmost concern. Previous studies suggested an increase in metabolic disorders in offspring later in life. The aim of the present study was to investigate metabolic changes at age 6-10 years in offspring conceived as a result of in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI). METHODS: A total of 380 children born from IVF/ICSI and a matched control group of 380 naturally conceived children, all aged 6-10 years, were recruited. Anthropometric measures, ultrasound and serum tests were performed for body mass, glucose metabolism and lipid profiles, and examination of vasculature structure. RESULTS: The children conceived by ART showed significantly higher fasting blood glucose and serum insulin levels and HOMA-IR (adjusted ß [95% CI]: fasting blood glucose 0.49 [0.42, 0.55]; loge-transformed insulin 0.28 [0.20, 0.35]; loge-transformed HOMA-IR 0.38 [0.30, 0.46]), as well as a lower HOMA-B and serum apolipoprotein A (ApoA) levels (adjusted ß [95% CI]: loge-transformed HOMA-B -0.19 [-0.27, -0.11]; ApoA -0.17 [-0.21, -0.13]), when compared with the control group. Furthermore, the ultrasound scan indicated elevated carotid intima-media thickness in children conceived by ART (ß 0.13 [95% CI 0.12, 0.13]). CONCLUSIONS/INTERPRETATION: Children conceived by IVF/ICSI have a less favourable glucose and cardiovascular metabolic profile in childhood when compared with naturally conceived children. The underlying mechanisms and potential long-term consequences need to be elucidated in future studies. Graphical abstract.

A novel electrochemical immunosensor for the highly sensitive and selective detection of the depression marker human apolipoprotein A4.

The fabrication of electrochemical biosensors to directly, rapidly and ultrasensitively detect disease markers in urine or blood samples has become a new and competitive challenge in the field of sensor research. In this paper, a novel electrochemical immunosensor with high selectivity and sensitivity for the detection of the depression marker human apolipoprotein A4 (Apo-A4) was successfully constructed using zeolite imidazole ester metal organic skeleton-nitrogen doped graphene composites (ZIF-8@N-Gr). To this end, because of the higher surface area and biocompatibility, ZIF-8 with abundant biomolecular binding sites provided a good microenvironment for effectively immobilizing antigens. ZIF-8@N-Gr presented a flake structure, as the electrode displayed excellent electrical conductivity, which enhanced the electron transfer and significantly amplified the current signal of the immunosensor. More importantly, these immunosensors are capable of assaying human apolipoprotein A4 (Apo-A4) in 100% serum without suffering from any significant biological interference. Under optimized experimental conditions, the sensor was used for the analysis of whole serum samples and presented a wide linear range from 1.47 × 10-10 g/mL to 3.00 × 10-7 g/mL with a low detection limit of 8.33 × 10-11 g/mL (3σ, n = 15). The satisfactory results of human serum sample analysis indicated that the proposed immunosensor had promising potential in the clinical diagnosis of depression.

Lipoprotein(a) and Apolipoproteins as Predictors for Diabetic Retinopathy and Its Severity in Adults With Type 2 Diabetes: A Case-Cohort Study.

OBJECTIVES: Our aim in this study was to assess the relationship between serum lipoprotein(a) [Lp(a)] and apolipoproteins and the risk of developing diabetic retinopathy (DR). METHODS: One thousand fifty-seven patients with type 2 diabetes were divided into 2 main groups and followed for 5 years: 637 patients without DR and 420 patients with DR. A group of patients with DR were then divided into 2 subgroups: 162 patients with nonproliferative DR (NPDR) and 163 patients with proliferative DR (PDR). The association between serum Lp(a) and apolipoproteins with NPDR and PDR was assessed using univariate and multivariate regression analyses. Receiver-operating characteristic curve analysis was performed based on the new cutoff values. RESULTS: There was a positive relationship between Lp(a) and the presence of DR as well as a negative correlation between ApoA and DR (p<0.001 and p=0.03, respectively). We also found a positive association between ApoB and the severity of DR (p=0.008). ApoA1 had an area under the curve of 55.0% for the prediction of DR. The calculated cutoff values of ApoB/ApoA1 ratio (0.58 g/L) and ApoB (77.5 g/L) in detection of DR were lower than their standard cutoff values of 0.8 and 90 g/L, respectively. Also, the sensitivity of new cutoff values for ApoB and ApoB/ApoA1 ratio was higher than the standard value, but the specificity of the standard cutoff values for both was higher than our new cutoff value. CONCLUSIONS: Serum Lp(a) and ApoA1 levels were independently associated with DR, and serum ApoB correlated with severity of DR. These measurements can be used for assessment and early treatment of this vision-threatening complication of diabetes.

Dysregulated serum lipid profile and its correlation to disease activity in young female adults diagnosed with systemic lupus erythematosus: a cross-sectional study.

BACKGROUND: Recent studies showed that dyslipidemia could be a critical factor in the progression of cardiovascular disease in systemic lupus erythematosus (SLE). The aim of the present study was to describe the relationship between serum lipid profile and SLE disease activity in young female adults with SLE. METHODS: Seventy-one female subjects diagnosed with SLE aged 20~30 years were enrolled. Serum lipid profile including TC, TG, HDL-C, LDL-C, VLDL-C, Apo A, Apo B, and Apo E were evaluated between control and young female SLE patients. Univariate correlation analyses were performed to explore the correlation between serum lipid levels and SLE disease activity. RESULTS: Our results showed that TG and VLDL-C levels were significantly increased in young female SLE as compared to control, with TC, HDL-C, LDL-C, Apo A, and Apo B significantly reduced. Meanwhile, univariate correlation analyses showed negative correlations between SLE disease activity index and HDL-C, LDL-C, Apo A, and Apo B; with positive correlations between SLE disease activity index and TG and VLDL-C. CONCLUSION: Serum lipid profile was significantly dysregulated in young female SLE patients. Moreover, SLE disease activity was correlated to the serum lipid levels, supporting the notion that the young patients with SLE might also have a higher risk of cardiovascular disease.

Apolipoprotein A-IV acts as an endogenous anti-inflammatory protein and is reduced in treatment-naïve allergic patients and allergen-challenged mice.

BACKGROUND: Recent studies pointed to a crucial role for apolipoproteins in the pathogenesis of inflammatory diseases. However, the role of apolipoprotein-IV (ApoA-IV) in allergic inflammation has not been addressed thoroughly thus far. OBJECTIVE: Here, we explored the anti-inflammatory effects and underlying signaling pathways of ApoA-IV on eosinophil effector function in vitro and in vivo. METHODS: Migratory responsiveness, Ca2+ -flux and apoptosis of human peripheral blood eosinophils were assessed in vitro. Allergen-driven airway inflammation was assessed in a mouse model of acute house dust mite-induced asthma. ApoA-IV serum levels were determined by ELISA. RESULTS: Recombinant ApoA-IV potently inhibited eosinophil responsiveness in vitro as measured by Ca2+ -flux, shape change, integrin (CD11b) expression, and chemotaxis. The underlying molecular mechanism involved the activation of Rev-ErbA-α and induced a PI3K/PDK1/PKA-dependent signaling cascade. Systemic application of ApoA-IV prevented airway hyperresponsiveness (AHR) and airway eosinophilia in mice following allergen challenge. ApoA-IV levels were decreased in serum from allergic patients compared to healthy controls. CONCLUSION: Our data suggest that ApoA-IV is an endogenous anti-inflammatory protein that potently suppresses effector cell functions in eosinophils. Thus, exogenously applied ApoA-IV may represent a novel pharmacological approach for the treatment of allergic inflammation and other eosinophil-driven disorders.

Downregulation of apolipoprotein A-IV in plasma & impaired reverse cholesterol transport in individuals with recent acts of deliberate self-harm.

Background & objectives: The major limiting factor in the prevention of suicide is the limited knowledge on molecular insights in individuals at risk. Identification of peripheral protein markers which can classify individuals at high-risk of suicide might aid in early diagnosis and effective medical intervention. The aim of the present study was, therefore, to analyze the differential regulation of plasma proteins in individuals with deliberate self-harm compared to controls. Methods: Using two-dimensional gel electrophoresis coupled with matrix-assisted laser desorption-ionization mass spectrometry, differentially expressed plasma proteins were identified in study participants with deliberate self-harm compared to age- and gender-matched controls. The finding was validated using mass spectrometry-based isotope-labelled relative quantification and Western blot analysis in a new set of individuals with deliberate self-harm and controls. Results: The plasma proteomic analysis showed that apolipoprotein A-IV (Apo A-IV ) was downregulated by 2.63-fold (confidence interval: 1.52-4.54) in individuals with deliberate self-harm (n=10) compared to matched controls, which was consistent in mass spectrometry-based relative quantification and Western blot analysis performed in an independent set of individuals with deliberate self-harm (n=18). In addition, plasma levels of total cholesterol, esterified cholesterol and high-density lipoprotein (HDL) were observed to be significantly lower individuals with deliberate self-harm compared to controls. Interpretation & conclusions: Apo A-IV, which plays a crucial role in the esterification of free cholesterol, was found to be downregulated with concomitantly decreased levels of HDL, esterified cholesterol and total cholesterol in individuals with deliberate self-harm compared to matched controls. The present findings might provide a link between the differential regulation of plasma proteins and the previously reported results on altered cholesterol levels in individuals with deliberate self-harm.

Prognostic value of serum high-density lipoprotein cholesterol in patients with gallbladder cancer

Objectives: the aim of this study was to evaluate the prognostic significance of preoperative serum lipid in patients with gallbladder cancer (GBC). Methods: ninety-nine patients with GBC between October 2009 and December 2013 were reviewed in this retrospective study. Total serum cholesterol (TC), total triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein A (Apo-A), apolipoprotein B (Apo-B) and free fatty acids (FFA) were measured before surgery. The correlation of serum lipid levels with clinical data, including gender, age, tumor size, lymph nodes metastasis, tumor differentiation, distant metastasis and TNM stage were analyzed by univariate and multivariate survival analysis to evaluate independent prognostic factors. Results: compared with the normal HDL-C group (n = 57), the overall survival rate among GBC patients with low HDL-C levels (n = 42) was reduced (p < 0.05). However, there were no significant differences in overall survival for patients with different levels of TC, TG, Apo-A, Apo-B, LDL-C or FFA. The serum level of HDL-C was associated with TNM stage (p < 0.05) and distant metastasis (p < 0.001). The multivariate prognosis analysis showed that HDL-C and lymph nodes metastasis were independent prognostic factors (p < 0.05). A prognostic evaluation model based on HDL-C and lymph nodes metastasis was established. Conclusion: preoperative serum HDL-C level was closely associated with distant metastasis of patients with GBC. HDL-C level may be a valuable prognostic factor for GBC patients. The combination of HDLC and lymph nodes metastasis can better predict the prognosis of GBC

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Biochemical Markers and Hypertension in Children.

INTRODUCTION Hypertension is one of the most studied risk factors for cardiovascular disease in adults; in children and adolescents, its global prevalence changes with age, from 1%-3% in children to 3.2% in adolescents. In adults, in addition to hypertension, several biochemical markers of cardiovascular risk have been identified. Confirming an association between these and hypertension in childhood and adolescence would allow for more timely diagnosis and monitoring of cardiovascular disease, since the presence of both the markers and hypertension would imply increased risk. OBJECTIVE Confirm an association between biochemical risk markers of cardiovascular disease and hypertension in children aged 8 to 11 years. METHODS A cross-sectional study of 373 children aged 8-11 years was conducted in 3 primary schools in the city of Santa Clara in central Cuba. The variables examined were age, sex, height, blood pressure, cholesterol, triglycerides, lipoproteins and apolipoproteins. The children were classified as normotensive, prehypertensive or hypertensive, based on blood pressure readings and percentiles for age, sex and height. Descriptive statistics were calculated for quantitative variables. A bivariate analysis, tests of independence for qualitative variables and a means comparison for quantitative variables (ANOVA and its nonparametric alternative, the Kruskal Wallis test) were performed. Fisher's F-test and its associated probability value were employed. RESULTS Some 32.2% of the children were prehypertensive and 5.1% hypertensive. Cholesterol and triglyceride values were significantly higher in hypertensive than in normotensive children (p = 0.028 and p = 0.047, respectively). HDL numbers were higher in normotensive children (p =0.001), and LDL numbers and the LDL/HDL ratio were higher in the hypertensive children, with differences between groups (p = 0.001 for both variables). There were differences between the three blood pressure categories for lipoprotein(a) and ApoA (p <0.001 and p = 0.001), for ApoB and for the ApoB/ApoA ratio (p <0.001 for both variables), with lower ApoA values and higher ApoB and ApoB/ApoA values in the hypertensive children. CONCLUSIONS The biochemical risk markers most strongly associated with hypertension in children are ApoB values, LDL, lipoprotein(a), and LDL/HDL and ApoB/ApoA ratios. KEYWORDS Adolescent, child, hypertension, apolipoproteins, cardiovascular diseases, risk factors, Cuba.