Early Disease Development Research Articles

Vascular Protective Effect and Its Possible Mechanism of Action on Selected Active Phytocompounds: A Review.

Vascular endothelial dysfunction is characterized by an imbalance of vasodilation and vasoconstriction, deficiency of nitric oxide (NO) bioavailability and elevated reactive oxygen species (ROS), and proinflammatory factors. This dysfunction is a key to the early pathological development of major cardiovascular diseases including hypertension, atherosclerosis, and diabetes. Therefore, modulation of the vascular endothelium is considered an important therapeutic strategy to maintain the health of the cardiovascular system. Epidemiological studies have shown that regular consumption of medicinal plants, fruits, and vegetables promotes vascular health, lowering the risk of cardiovascular diseases. This is mainly attributed to the phytochemical compounds contained in these resources. Various databases, including Google Scholar, MEDLINE, PubMed, and the Directory of Open Access Journals, were searched to identify studies demonstrating the vascular protective effects of phytochemical compounds. The literature had revealed abundant data on phytochemical compounds protecting and improving the vascular system. Of the numerous compounds reported, curcumin, resveratrol, cyanidin-3-glucoside, berberine, epigallocatechin-3-gallate, and quercetin are discussed in this review to provide recent information on their vascular protective mechanisms in vivo and in vitro. Phytochemical compounds are promising therapeutic agents for vascular dysfunction due to their antioxidative mechanisms. However, future human studies will be necessary to confirm the clinical effects of these vascular protective mechanisms.

The critical role of epigenetic mechanisms involved in nanotoxicology.

Over the past decades, nanomaterials (NMs) have been widely applied in the cosmetic, food, engineering, and medical fields. Along with the prevalence of NMs, the toxicological characteristics exhibited by these materials on health and the environment have gradually attracted attentions. A growing number of evidences have indicated that epigenetics holds an essential role in the onset and development of various diseases. NMs could cause epigenetic alterations such as DNA methylation, noncoding RNA (ncRNA) expression, and histone modifications. NMs might alternate either global DNA methylation or the methylation of specific genes to affect the biological function. Abnormal upregulation or downregulation of ncRNAs might also be a potential mechanism for the toxic effects caused by NMs. In parallel, the phosphorylation, acetylation, and methylation of histones also take an important part in the process of NMs-induced toxicity. As the adverse effects of NMs continue to be explored, mechanisms such as chromosomal remodeling, genomic imprinting, and m6 A modification are also gradually coming into the limelight. Since the epigenetic alterations often occur in the early development of diseases, thus the relevant studies not only provide insight into the pathogenesis of diseases, but also screen for the prospective biomarkers for early diagnosis and prevention. This review summarizes the epigenetic alterations elicited by NMs, hoping to provide a clue for nanotoxicity studies and security evaluation of NMs. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

Glycoprotein Acetyls: A Novel Inflammatory Biomarker of Early Cardiovascular Risk in the Young.

BackgroundLow‐grade inflammation in the young may contribute to the early development of cardiovascular disease. We assessed whether circulating levels of glycoprotein acetyls (GlycA) were better able to predict the development of adverse cardiovascular disease risk profiles compared with the more commonly used biomarker high‐sensitivity CRP (C‐reactive protein).Methods and ResultsA total of 3306 adolescents and young adults from the Avon Longitudinal Study of Parents and Children (mean age, 15.4±0.3; n=1750) and Cardiovascular Risk in Young Finns Study (mean age, 32.1±5.0; n=1556) were included. Baseline associations between inflammatory biomarkers, body composition, cardiovascular risk factors, and subclinical measures of vascular dysfunction were assessed cross‐sectionally in both cohorts. Prospective risk of developing hypertension and metabolic syndrome during 9‐to‐10‐year follow‐up were also assessed as surrogate markers for future cardiovascular risk. GlycA showed greater within‐subject correlation over 9‐to‐10‐year follow‐up in both cohorts compared with CRP, particularly in the younger adolescent group (r=0.36 versus 0.07). In multivariable analyses, GlycA was found to associate with multiple lifestyle‐related cardiovascular disease risk factors, cardiometabolic risk factor burden, and vascular dysfunction (eg, mean difference in flow‐mediated dilation=−1.2 [−1.8, −0.7]% per z‐score increase). In contrast, CRP levels appeared predominantly driven by body mass index and showed little relationship to any measured cardiovascular risk factors or phenotypes. In both cohorts, only GlycA predicted future risk of both hypertension (risk ratio [RR], ≈1.1 per z‐score increase for both cohorts) and metabolic syndrome (RR, ≈1.2–1.3 per z‐score increase for both cohorts) in 9‐to‐10‐year follow‐up.ConclusionsLow‐grade inflammation captured by the novel biomarker GlycA is associated with adverse cardiovascular risk profiles from as early as adolescence and predicts future risk of hypertension and metabolic syndrome in up to 10‐year follow‐up. GlycA is a stable inflammatory biomarker which may capture distinct sources of inflammation in the young and may provide a more sensitive measure than CRP for detecting early cardiovascular risk.

Abemaciclib: The First FDA-Approved CDK4/6 Inhibitor for the Adjuvant Treatment of HR+ HER2- Early Breast Cancer.

To review the new indication of cyclin-dependent kinase (CDK4/6) inhibitor abemaciclib for the adjuvant treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), axillary lymph node (LN) positive early breast cancer (EBC) at high risk of recurrence and a Ki-67 ≥20%. A literature search was performed through PubMed, ClinicalTrials.gov, and Food and Drug Administration (FDA) website (February 1, 2018, to December 23, 2021) to identify relevant information. Human and animal studies related to pharmacology, pharmacokinetics, efficacy, and safety of abemaciclib were identified. Addition of abemaciclib to standard of care endocrine therapy (ET) for patients with high-risk clinicopathologic features and Ki-67 ≥20% demonstrated 30% reduction in the risk of developing invasive disease and distant recurrence. At 15.5 months, abemaciclib + ET demonstrated a significant improvement in invasive disease-free survival (IDFS) vs ET alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60-0.93, P = 0.01). At 27 months, IDFS benefit was maintained (HR, 0.70; 95% CI, 0.59-0.82, P < 0.0001). Diarrhea occurred in more than 80% of patients in the abemaciclib arm. This review describes the clinical applicability of adjuvant abemaciclib for patients with HR+, HER2- EBC at high risk for recurrence. Adjuvant abemaciclib significantly reduces the risk for early development of invasive disease and distant recurrence in patients with HR+, HER2- node positive EBC. Longer follow-up is needed to determine the impact of adjuvant abemaciclib on late disease recurrence and survival outcomes.

Tailoring ZnO nanowire crystallinity and morphology for label-free capturing of extracellular vesicles.

Zinc oxide (ZnO) nanowires have shown their potential in isolation of cancer-related biomolecules such as extracellular vesicles (EVs), RNAs, and DNAs for early diagnosis and therapeutic development of diseases. Since the function of inorganic nanowires changes depending on their morphology, previous studies have established strategies to control the morphology and have demonstrated attainment of improved properties for gas and organic compound detection, and for dye-sensitized solar cells and photoelectric conversion performance. Nevertheless, crystallinity and morphology of ZnO nanowires for capturing EVs, an important biomarker of cancer, have not yet been discussed. Here, we fabricated ZnO nanowires with different crystallinities and morphologies using an ammonia-assisted hydrothermal method, and we comprehensively analyzed the crystalline nature and oriented growth of the synthesized nanowires by X-ray diffraction and selected area electron diffraction using high resolution transmission electron microscopy. In evaluating the performance of label-free EV capture in a microfluidic device platform, we found both the crystallinity and morphology of ZnO nanowires affected EV capture efficiency. In particular, the zinc blende phase was identified as important for crystallinity, while increasing the nanowire density in the array was important for morphology to improve EV capture performance. These results highlighted that the key physicochemical properties of the ZnO nanowires were related to the EV capture performance.

Association of Serum Adiponectin Level with Dyslipidaemia in North Indian Male Population: A Case-control Study

Introduction: Adiponectin is the most abundant adipocytokines secreted from adipose tissues and circulates in considerably high concentration in human plasma. Circulating adiponectin levels are decreased in obese subjects and this decrease has been thought to play a crucial role in the early development of atherosclerosis and cardiovascular diseases. Changes in adiponectin concentration has been reported in dyslipidemic subjects, but the evidence is controversial and no study conducted in north Indian population. Moreover, low molecular adiponectin seems to be linked with a worse lipid profile leading to dyslipidaemic through an association with triglyceride but the exact role of adiponectin in modulating lipid fraction is not well established. Aim: To correlate the level of serum adiponectin with lipid fractions in dyslipidemic male subjects and also to compare them with apparently healthy individuals. Materials and Methods: This case control study was conducted from April 2015 to November 2016 in the Biochemistry department of Rajshree Medical Research institute, Bareilly, Uttar Pradesh, India. A total of 70 non diabetic dyslipidemic male subjects between the age group 35 years to 55 years were selected and all the biochemical parameters (adiponectin, fasting plasma glucose, lipid profile) were evaluated and compared with 70 apparently healthy controls. Statistical analysis was performed by licensed version of Statistical Package for Social Sciences (SPSS) 16.0 software. All the data were expressed in “mean±SD”. Student ‘t’ test was also applied to see statistical significance in adiponectin levels between dyslipidemic subjects and healthy controls. Results: The study shows mean±SD of age in dyslipidemic group was 43.61±4.85 years and for control group was 43.53±5.53 years. The mean±SD of BMI in dyslipidemic group 25.72±2.43 was significantly higher than control group 23.42±1.56 with p-value &lt;0.0001. The serum adiponectin concentration was significantly reduced in dyslipidemic subjects 5.11±2.04 μg/mL as compared to healthy control 6.79±1.37 μg/mL with p-value &lt;0.0001. Serum total cholesterol, triglyceride and Low Density Lipoprotein (LDL)- cholesterol were found to be negatively correlated with serum adiponectin (r= -0.89, -0.76 and -0.74) and positively correlated with High Density Lipoprotein (HDL)-cholesterol (r= 0.70). Conclusion: The present study revealed that hypoadiponectinemia is associated with dyslipidaemic in men. The main observation of our present study, however, is that in dyslipidemic subjects, lower levels of adiponectin were associated with high total cholesterol, triglyceride, LDL-cholesterol and reduced HDL cholesterol, though more extensive, multicentric, prospective research with increase sample size could obtain wider insights.

Comparative Analysis of the Chemical Composition of Natural Waters in the Khanty-Mansiysky and Yamalo-Nenets Autonomous Districts

Background: Water is a key source of life on Earth; it is involved in the transfer of nutrients, macro- and microelements between soil, plants, animals and humans, as well as in the concentration and dispersion of chemical elements and the formation of minerals. The elemental status of the population is largely determined by the chemical composition of the natural waters on the territory of residence. Objective: To perform a comparative analysis of the concentrations of iron, manganese, calcium and magnesium in natural waters of the Khanty-Mansiysk and Yamalo-Nenets Autonomous Districts (Okrugs). Materials and methods: We established concentrations of iron, manganese, calcium and magnesium in 100 samples of natural waters taken from rivers, lakes, backwaters, channels, etc. of the Khanty-Mansiysk and Yamalo-Nenets Autonomous Districts, 50 samples each, using spectrophotometry, capillary electrophoresis and atomic absorption spectrometry. The results obtained were compared with the reference values provided in Russian sanitary rules and regulations SanPiN 1.2.3685–21. Results: We established elevated levels of iron in most surface water samples from both districts and of manganese in the Khanty-Mansi Autonomous Okrug accompanied by extremely low concentrations of Ca and Mg in the vast majority of all samples. At the same time, we registered significantly lower concentrations of Ca (p = 0.012) and Mg (p = 0.021) in the water samples from the Yamalo-Nenets Autonomous Okrug compared to those from the other district. Conclusion: In the population of the Tyumen North, the constant use of such water for drinking purposes can lead to the early development and rapid progression of cardiovascular and osteoarticular diseases, type 2 diabetes, neoplasms, etc.; at the same time, people are at risk of generalization of immunosuppressive conditions, diseases of the central nervous system, gastrointestinal tract, oxidative metabolism disorders, etc.

Early development of extramedullary disease in multiple myeloma with no high-risk chromosomal abnormalities and good clinical course

Early development of extramedullary disease in multiple myeloma with no high-risk chromosomal abnormalities and good clinical course

Alteration of Hematological and Biochemical Parameters to Predict Severity in SARS-CoV-2 Infection

Introduction: SARS- CoV-2 global pandemic has fired the world into a notable health catastrophe, with over 187,348,181 cases and 4,044,898 deaths as of July 10 2021. Many studies have been conducted to determine the clinical, biological, and radiological characteristics of COVID-19 for better identification of infected people at an early stage and stop disease development to an advanced state. Objectives: The aim &amp; objective of our study was to take advantage of the biochemical and hematological parameters in pre-dicting the prognosis and mortality in disease severity COVID-19 patients. Methods: This single-center retrospective, observational study was supervised to have all the admitted patients (n = 90) possessing COVID-19 Polymerase chain reaction (PCR) positive, and assessed those for prognosis and disease outcome by taking advantage of several biochemical and hematological markers. Results: Out of 90 patients, 53(58.89%) had mild to moderate disease that were included in the non-severe group; 37(41.11%) had severe to critical disease, of which 17 died and 20 survived. Advanced age, presence of comorbidities and infection were risk factors for advancement to severe disease. The existence of statistically significant abnormalities in the following parameters were strongly related with the advancement to severe disease: white blood cells (WBC, p=0.002), neutrophils (p=0.001), lymphocytes (p=0.001), C-reactive protein (CRP, P&lt;0.001), D-dimer (P&lt;0.001), Lactate dehydrogenase (LDH, p&lt;0.001), Ferritin (P&lt;0.001), creatinine (p=0.001), aspartate aminotransferase (AST, P=0.012), procalcitonin (P&lt;0.001) and alanine aminotransferase (ALT, P=0.001) during both admission and hospitalization. Conclusion: The inflammatory markers, biochemical parameters and hematological indices are a good guide for predicting the severity and disease outcome of coronavirus disease.

The influence of mother's diseases and complications of pregnancy on the development of allergic reactions in neonates and infants

The article reviews the materials dealing with the role of mothers diseases, complications of pregnancy, and unfavorable environmental factors in formation of immunological reactions in neonates. The author emphasizes the role of disturbances of afterbirth state in case of gestosis, infections, mothers smoking.Peculiarities of immune mechanisms of neonates compared with those of elder children determine their reactivity and early development of allergic diseases.

Networks of free-living nematodes and co-extracted fungi, associated with symptoms of apple replant disease

Apple replant disease affects tree nurseries and apple production globally. After repeated planting in the same soil, apple roots show accumulation of phytoalexins, stunting, and blackening. Recently, we showed that nematodes extracted from replanted soil and co-extracted microbes triggered these symptoms, while pathogens or plant-parasitic nematodes could not explain the early disease development. To identify nematode-microbe complexes that coincide with replant disease, apple rootstocks were grown in the greenhouse in soils from five replanted sites for eight weeks. Nematodes were extracted by floatation from pots with stunted or normal plant growth, washed on a 20-μm sieve, and used for DNA extraction. Nematode communities and co-extracted fungi and bacteria were analyzed by high-throughput sequencing of amplified ribosomal fragments. The experiment was repeated in the next year. Regardless of soil type or year, the nematode and fungal communities significantly differed between pots with differential plant growth. Bacteria were not significantly associated with growth depression. Plant-parasitic nematodes or pathogens were not abundant in numbers that could explain the observed root damage. Free-living nematodes Prsimatolaimus, Acrobeles, Tylencholaimus, Acrobeloides, and Aphelenchus, and associated fungi Exophiala, Hohenbuehelia, Naganishia, Psathyrella, and unidentified members of Orbiliales, Helotiales, and Rhytismataceae significantly correlated with reduced plant growth. Isolating and investigating such disease complexes will give a chance to understand external biotic stress of apple roots and design mitigation measures.

Long-term Physical Exercise Improves Finger Tapping of Patients with Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease that has been characterized by progressive development of long onset early disease with complicated etiology and may cause memory loss, cognitive impairment, and behavioral changes. Physical exercise may play a preventive role in AD. In the present study, we investigated the impact of longer-term physical exercise on the finger tapping of AD patients by comparing the finger tapping of AD patients and healthy controls. In this study, 140 subjects aged ≥ 60 years were enrolled. Group A consisted of 70 subjects (27 males and 43 females) without exercise habits who were selected from Yangpu District (Shanghai, China). Group B consisted of 70 subjects (27 males and 43 females) who were selected from Minxing District (Shanghai, China). All the subjects were right-handed as well. The subjects' data, including subjects' age, weight, height, Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), and finger tapping frequency, were measured. The subjects were matched in age, weight, and height. The AD subjects' MoCA and MMSE scores were noticeably lower than healthy subjects' scores (P<0.001); besides, AD patients with exercise had significantly lower MoCA and MMSE scores than healthy controls with exercise (P<0.001). The finger tapping of AD subjects' left hands was significantly lower than that of healthy subjects without AD (P<0.01), and AD subjects with exercise tapped significantly slower with their left hand than healthy subjects with exercise (P<0.01). Meanwhile, AD subjects with exercise tapped significantly faster with the left hand than AD subjects (P<0.05). The right hands of AD subjects tapped remarkably less than healthy subjects (P<0.01) with or without exercise. Meanwhile, subjects with exercise tapped significantly faster with their right hand than healthy subjects (P<0.05), and AD subjects with exercise tapped significantly faster with their right hand than AD subjects (P<0.05). Long-term physical exercises can improve finger tapping frequency, especially in patients with AD. Finger tapping frequency may be used as an index to monitor the cognitive decline in ageing AD patients.

Risk factors for multidrug-resistant bacterial infections in patients with diabetic foot ulcers: a systematic review and meta-analysis.

Diabetic foot ulcer (DFU) is one of the main causes of disability and death in diabetic patients, along with the continuous development of relevant research. The purpose of this paper is to study the risk factors of multidrug resistant organisms (MDROs) infection in patients with DFUs by meta-analysis. We searched the PubMed, EMBASE, Cochrane library, and Web of Science databases for literature related to the risk factors of MDRO infection in patients with DFUs from the date of establishment of the database to September 2021. Duplicate studies were excluded using Endnote X9 software. Stata 15.1 software was used to meta-analyze the data. Random or fixed effects models were used to combine and analyze the odds ratio (OR) and 95% confidence interval (CI) of the included risk factors. Heterogeneity was analyzed by the Q and I2 tests. Egger's linear regression method was used to evaluate the publication bias of the included articles. Sensitivity analysis was used to analyze the source of heterogeneity. A total of 13 articles were included in the study. Meta-analysis was performed on 15 risk factors. Among them, hospital records before admission (OR =5.18, 95% CI: 1.45-18.51, P=0.011), antibiotic use before admission (OR =2.17, 95% CI: 1.24-3.79, P=0.006), diabetes type (OR =2.44, 95% CI: 1.29-4.64, P=0.006), ulcer type (OR =2.17, 95% CI: 1.06-4.41, P=0.033), ulcer size (OR =2.56, 95% CI: 1.53-4.28, P<0.001), osteomyelitis (OR =3.50, 95% CI: 2.37-5.16, P<0.001), vascular disease (OR =2.37, 95% CI: 1.41-3.99, P=0.001), surgical treatment (OR =4.80, 95% CI: 2.95-7.83, P<0.001), and these meta-analysis results were statistically different and could be considered as risk factors for MDRO infection. The risk factors of MDRO infection in DFU patients include hospitalization records before admission, antibiotic use before admission, type of diabetes, type of ulcer, size of ulcer, osteomyelitis, vascular lesions, and surgical treatment. This study contributes to the ability of the population of DFU patients infected with MDROs to receive timely treatment at an early stage and delay disease development.

Data alignment to model Alzheimer's disease (AD).

Alzheimer's disease (AD) is a heterogenous disease that is associated with complex brain changes and major alterations in gene expression. The analysis of correlated transcriptomic variation can help in understanding the biological mechanisms underlying the disease. Having a comprehensive atlas of changes in human brain transcriptome, enables the application of data alignment to other models like mouse to validate, assess, and compare such changes. Identifying the optimal mouse model can further advance the discovery of the early disease characteristics and development of potential drugs. Our methodology starts by considering distinct human late-onset AD (LOAD) subtypes based on case heterogeneity, each is examining a specific group of molecular profiles. Moreover, we performed comprehensive transcriptome profiling of brains from a panel of early-onset AD (EOAD) mouse models at 8 months of age, including six distinct genetic backgrounds carrying the same APP/PS1 transgenic construct. Next, we generate informative features that determine the specific characteristic in each population of samples in mouse and human. Then, we identify and measure the overall relationships between human and mouse via the dimension reduction technique canonical correlation analysis. By cross-aligning samples, we are able to identify which mouse model shows correlated changes with which human subtype. Finally, we identify and rank the major translatable altered pathways in which the mouse model effects mimic disease effects in human subtypes. The selected set of pathways represents AD-related pathway modifications that varies across mouse models. Moreover, based on the gene overlap, this ranked set of pathways reveals cell-type-specific pathways associated with LOAD pathogenesis in the brain. Our results suggested that cross-species data alignment reveals similar samples between human and mouse populations. We identify the potential mouse models, with the potential AD-related pathways that have similar genetic characteristics to human subtypes. We believe that using diverse mouse models to model AD in human can better recapitulate the molecular changes during the origin and progression of LOAD.

Клініко-лабораторні та генетичні паралелі у хворих з гетеро- та гомозиготними сімейними гіперхолестеринеміями в Україні

The aim – clinical, laboratory and genetic parallels of patients with hetero- and homozygous familial hypercholesterolemia (FH) in Ukraine.Materials and methods. 231 FH patients were included in the Ukrainian FH Registry: 8 children (under 18 years of age) and 223 adult patients (197 heterozygous FH (HeFH) patients, 26 homozygous FH (HoFH) patients, verified according to DLCN criteria). The patients underwent general clinical, laboratory, instrumental examinations and genetic testing.Results and discussion. Among HeFH patients against the background of early manifestation of atherosclerosis, the male patients were more likely to have coronary heart disease and peripheral atherosclerosis, xanthomatosis and higher DLCN scores against an increase in % obesity and hypertension among HeFH women on the background of significantly lower DLCN. In the HoFH patients despite the inclusion of mostly reproductive aged females in the Registry, it is among women the most severe variants of FH were registered. They were characterized by a predominance of coronary heart disease, MI, xanthomatosis, the need for myocardial revascularization and prosthetic heart valves on the background of higher DLCN scores, cholesterol, LDL-C and ApoB values ​​up to 1.7±0.2 g/L and Lp (a) up to 119.5±31.4 nmol/L. In HoF patients and the most severe variants of the clinical course, who had levels of «statin naive» cholesterol and LDL above 20 mmol/L a more significant increase in these values were found: ApoB average 3.2±1.1 (maximum – 4.72) g/L and Lp (a) to 121.5±41.5 (maximum – 163) nmol/L and reduction of apoA1 level to 0.9±0.1 g/L.Conclusions. HeFH patients retain gender features of the risk factors profile, which corresponds to the main gender-related trends revealed by the Ukrainian population study with a predominance of coronary heart disease, peripheral atherosclerosis and xanthomatosis on the background of higher scores on DLCN in men. HoFH patients showed a reverse trend, namely among women – the predominance of coronary heart disease, myocardial infarction, xanthomatosis and the need for revascularization on the background of a higher score on DLCN. The cohort of HoFH women revealed the most severe FH cases with LDL-C &gt; 20 mmol/L, which was accompanied in 100 % of cases by early development of coronary heart disease and the need for myocardial revascularization, despite young age (36.5±3.9) and preserved reproductive function. According to HoFH patients genetic testing, pathogenetic mutations were detected in 72.3 % of women and 55.5 % of men (92.3 % in LDLR and 7.7 % in apoB). In the cohort of the most severe patients with LDL and LDL cholesterol &gt; 20 mmol/L, genetic mutations were detected in 100 %

Higth-sensitivity T troponin and NT pro B-type natriuretic peptide as predictors of early development of structural heart disease in patients with stage 0 of Chagas disease

Abstract Background Approximately 30% of patients with Chagas disease (ChD) develop structural heart disease at some point in their evolution. There is an asymptomatic period where there is no evidence of cardiac involvement, called stage 0. Prognostic evaluation in this group of patients remains a challenge. On the other hand, the presence of elevated hight-sensitivity T troponin (HS-TnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) has been documented in the early stages of the ChD. The role of these biomarkers as predictors of early development of structural heart disease in the follow-up of stage 0 ChD has been poorly studied. Purpose The aim of this study is to evaluate if HS-TnT and NT-proBNP are a predictor of early development of cardiac structural alterations in the follow up of patients with stage 0 ChD. Materials and methods Outpatients with stage 0 of ChD (positive serology, with normal electrocardiogram, 24-hours holter and echocardiogram) were included prospectively. Baseline measurement of HS-TnT and NT-proBNP was performed. The follow-up was carried out with serial echocardiography and 24-hour Holter. The end point of development of structural heart disease was considered, defined as one of the following: left ventricular dilation (diastolic diameter of left ventricle &amp;gt;60 mm in men or &amp;gt;55 mm in women), deterioration of ventricular function (Drop &amp;gt;10 points of Left Ventricular Ejection Fraction (LVEF) or LVEF &amp;lt;50%), Complex ventricular arrhythmia or Atrio-ventricular block ≥ second degree Mobitz II. Univariate and multivariate analysis was performed by cox regression. Results Three hundred two patients were included, with 47±9 years old, 46% woman. With a median of follow-up of 34 (interquartile range 19 – 43) months, the end point of development of structural heart disease was presented in 4.6% (n=14 patients). In multivariate analysis both HS-TnT and NT-ProBNP were independent predictors of development of structural heart disease [HR 1.18 (IC95% 1.05–1.33), p=0.003 and HR 1.01 (CI95% 1.00–1.01), p=0.001; respectively]. The area under the Receiver operating characteristic (ROC) curve was calculated, for HS-TnT it was 0.80 (95% CI 0.65–0.93), with a cut-off point for HS-TnT &amp;gt;14 ng/ml and for NT-proBNP it was 0.88 (95% CI 0.83–0.95) with a cut-off point for NT-proBNP &amp;gt;200 pg/ml. The figure shows the Kaplan-Meier curve for HS-TnT and NT-proBNP. In adjusted analysis, HS-TnT &amp;gt;14 ng/ml had a HR 5.27 (CI95% 1.4–18.9), p=0.01 and NT-proBNP HR 3.07 (CI95% 1.01–10.9), P=0.04. Conclusions In our population of patients with stage 0 chagas disease, HS-TnT and NT-proBNP were independent predictors of early development of structural heart disease, with good predictive capacity. The baseline measurement of these biomarkers can be useful in the evaluation and follow-up of patients with ChD without initial evidence of cardiac involvement. Funding Acknowledgement Type of funding sources: None. Kaplan-Meier curve

A possible association between early life factors and burden of functional bowel symptoms in adulthood

Objective The studies of early life factors and development of functional bowel diseases show inconsistent results. We therefore examined associations between certain early life factors and functional bowel symptoms in adulthood. Design Population-based cross-sectional study. Setting Weight and height were measured and questionnaires were completed at the time point of enrollment in MOS. Subjects 1013 participants in the Malmö Offspring Study (MOS) without organic bowel disease with data available from the Swedish Medical Birth Registry. Main outcome measures Associations were calculated between gestational age, birth weight, small-for-gestational-age and Apgar score from the Birth Registry, and symptoms according to the visual analog scale for irritable bowel syndrome (VAS-IBS) (abdominal pain, diarrhea, constipation, bloating and flatulence, vomiting and nausea, and symptoms’ influence on daily life) or self-reported IBS using logistic regression. Results In all, 253 (25.0%) participants reported bowel symptoms during the past 2 weeks and 179 (17.7%) self-reported IBS; conditions which were strongly associated (p < 0.001). Female sex and chronic stress were two independent factors more common among participants with bowel symptoms compared with asymptomatic participants (p < 0.001). Early life factors were not associated with presence of overall bowel symptoms (p = 0.080), any specific bowel symptoms or self-reported IBS. Lower birth weight (p = 0.038) and being born small for gestational age (p = 0.043) were associated with severe influence of intestinal symptoms on daily life in adulthood. Conclusions Lower birth weight and small for gestational age are not associated with the presence of overall bowel symptoms but with more pronounced influence of such symptoms on daily adult life. Key points Lower gestational age tended to be associated with functional bowel symptoms in adulthood. Lower birth weight and being small for gestational age are associated with increased negative influences of symptoms on daily life in adulthood. Patients born preterm or with low birth weights may be at increased risk to develop functional bowel symptoms later in life.

Clinical Features of Familial Hypercholesterolemia in Children and Adults in EAS-FHSC Regional Center for Rare Diseases in Poland.

Background: Familial hypercholesterolemia (FH) is a genetic autosomal co-dominant metabolic disorder leading to elevated circulating concentrations of low-density lipoprotein cholesterol (LDL-C). Early development of atherosclerotic cardiovascular disease (ASCVD) is common in affected patients. We aimed to evaluate the characteristics and differences in the diagnosis and therapy of FH children and adults. Methods: All consecutive patients who were diagnosed with FH, both phenotypically and with genetic tests, were included in this analysis. All patients are a part of the European Atherosclerosis Society FH-Study Collaboration (FHSC) regional center for rare diseases at the Polish Mother’s Memorial Hospital Research Institute (PMMHRI) in Lodz, Poland. Results: Of 103 patients with FH, there were 16 children (15.5%) at mean age of 9 ± 3 years and 87 adults aged 41 ± 16; 59% were female. Children presented higher mean levels of total cholesterol, LDL-C, and high-density lipoprotein cholesterol (HDL-C) measured at the baseline visit (TC 313 vs. 259 mg/dL (8.0 vs. 6.6 mmol/L), p = 0.04; LDL 247 vs. 192 mg/dL (6.3 vs. 4.9 mmol/L), p = 0.02, HDL 53 vs. 48 mg/dL (1.3 vs. 1.2 mmol/L), p = 0.009). Overall, 70% of adult patients and 56% of children were prescribed statins (rosuvastatin or atorvastatin) on admission. Combination therapy (dual or triple) was administered for 24% of adult patients. Furthermore, 13.6% of adult patients and 19% of children reported side effects of statin therapy; most of them complained of muscle pain. Only 50% of adult patients on combination therapy achieved their treatment goals. None of children achieved the treatment goal. Conclusions: Despite a younger age of FH diagnosis, children presented with higher mean levels of LDL-C than adults. There are still urgent unmet needs concerning effective lipid-lowering therapy in FH patients, especially the need for greater use of combination therapy, which may allow LDL-C targets to be met in most of the patients.

Abstract 29: Acute Systemic Treatment With Sphingosine -1- Phosphate Receptor 1 Agonist Diminishes Sex-difference In Renal Function Seen In Intrauterine Growth Restricted Mice.

IUGR is a risk factor for the early development of cardiorenal diseases in life. We previously showed that our IUGR mouse model exhibits sex differences in blood pressure (BP) and kidney functions as males have elevated BP and impaired kidney function while females are not. Sphingosine-1-Phosphate Receptor 1 (S1PR1) is reported to be involved in developing and progressing several cardiorenal diseases. We found that acute activation of S1PR1 transiently reduced BP in male IUGR; however, the effects of SIPR1 on renal function in IUGR are still unknown. We hypothesize that S1PR1 plays a role in the sex differences of impaired kidney function in IUGR. Here we investigated the acute effects of a specific S1PR1 agonist (SEW2178) on kidney function in IUGR offspring generated through placental insufficiency. Methods: C57BL IUGR or control offspring were obtained from the Reduced Uterine Perfusion Pressure (RUPP) or sham surgeries on the 13 th day of gestation. At 6 months, nephron number was measured by analyzing kidney histology while Glomerular Filtration Rate (GFR) was measured using FITC-Anulin decay after retroorbital injection. Mice were treated with 3mg/kg SEW2871 i.p before GFR measurement. Results: Both male and female IUGR had a decrease in nephron number compared to same-sex control (371.8± 28.8 vs 284.0± 11.3, P&lt;0.01, male control vs IUGR) and (333.6±13.3 vs 256± 13.0, P&lt;0.05, female control vs IUGR). Furthermore, IUGR impaired kidney function in male but not female mice as indicated by reduced GFR (8.9 ±0.6 vs 13.9±1.1 μL/min/kg BW, P&lt;0.05, IUGR vs control males) and (12.3±0.9 vs 15.9 ±1.9 L/min/kg BW, control females vs IUGR). Administration of SEW2871 diminished the difference of GFR between male control and IUGR (9.5±0.6 vs 9.7±1.1 μL/min/kg BW, P&gt; 0.05 control vs IUGR). While in females, both IUGR and control had a similar response to SEW2178 (7.4±1.0 vs 10.6 ±1.9 μL/min/kg BW, control vs. IUGR). Conclusion: IUGR impairs renal function in male offspring but not in females, indicating sex differences in fetal programming of kidney disease. Male and female IUGR offspring respond differently to acute systemic activation of S1PR1. Further studies are required to investigate the kidney-specific and cell-specific of S1PR1 activation/inhibition.

Genomic Diversity and Antimicrobial Resistance of Haemophilus Colonizing the Airways of Young Children with Cystic Fibrosis.

Respiratory infection during childhood is a key risk factor in early cystic fibrosis (CF) lung disease progression. Haemophilus influenzae and Haemophilus parainfluenzae are routinely isolated from the lungs of children with CF; however, little is known about the frequency and characteristics of Haemophilus colonization in this context. Here, we describe the detection, antimicrobial resistance (AMR), and genome sequencing of H. influenzae and H. parainfluenzae isolated from airway samples of 147 participants aged ≤12 years enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program, Melbourne, Australia. The frequency of colonization per visit was 4.6% for H. influenzae and 32.1% for H. parainfluenzae, 80.3% of participants had H. influenzae and/or H. parainfluenzae detected on at least one visit, and using genomic data, we estimate 15.6% of participants had persistent colonization with the same strain for at least two consecutive visits. Isolates were genetically diverse and AMR was common, with 52% of H. influenzae and 82% of H. parainfluenzae displaying resistance to at least one drug. The genetic basis for AMR could be identified in most cases; putative novel determinants include a new plasmid encoding blaTEM-1 (ampicillin resistance), a new inhibitor-resistant blaTEM allele (augmentin resistance), and previously unreported mutations in chromosomally carried genes (pbp3, ampicillin resistance; folA/folP, cotrimoxazole resistance; rpoB, rifampicin resistance). Acquired AMR genes were more common in H. parainfluenzae than H. influenzae (51% versus 21%, P = 0.0107) and were mostly associated with the ICEHin mobile element carrying blaTEM-1, resulting in more ampicillin resistance in H. parainfluenzae (73% versus 30%, P = 0.0004). Genomic data identified six potential instances of Haemophilus transmission between participants, of which three involved participants who shared clinic visit days. IMPORTANCE Cystic fibrosis (CF) lung disease begins during infancy, and acute respiratory infections increase the risk of early disease development and progression. Microbes involved in advanced stages of CF are well characterized, but less is known about early respiratory colonizers. We report the population dynamics and genomic determinants of AMR in two early colonizer species, namely, Haemophilus influenzae and Haemophilus parainfluenzae, collected from a pediatric CF cohort. This investigation also reveals that H. parainfluenzae has a high frequency of AMR carried on mobile elements that may act as a potential reservoir for the emergence and spread of AMR to H. influenzae, which has greater clinical significance as a respiratory pathogen in children. This study provides insight into the evolution of AMR and the colonization of H. influenzae and H. parainfluenzae in a pediatric CF cohort, which will help inform future treatment.