Low Serum Concentrations Research Articles

Effects of CYP2C19 genetic polymorphisms on the pharmacokinetics of lacosamide in Korean patients with epilepsy.

Many pharmacokinetic studies of lacosamide (LCM) have been reported, but no large-scale clinical study has been conducted on genetic polymorphisms that affect the metabolism of LCM. Therefore, we designed a pharmacogenetic study of LCM to explore the effect of genetic polymorphisms on serum LCM concentration. We evaluated the pharmacodynamic characteristics of LCM, including clinical efficacy and toxicity. Adult patients with epilepsy who received LCM at Seoul National University Hospital were enrolled. Blood samples were obtained from 115 patients taking LCM for more than 1 month with unchanged doses and were used to analyze the serum LCM concentration, the concentration/dose (C/D) ratio and the single nucleotide polymorphisms (SNPs) of the cytochrome P450 (CYP)2C9 and CYP2C19 genes. In addition, clinical information-including efficacy, toxicity, and concomitant drugs-was collected. The serum LCM concentration showed a linear correlation with the daily dose (r=.66, p < .001). In genetic analysis, 43 patients (38.7%) were extensive metabolizers (EMs), 51 (45.9%) were intermediate metabolizers (IMs), and 17 (15.3%) were poor metabolizers (PMs). In the group comparison, mean serum concentrations and the C/D ratio showed significant differences between the three groups (p=.01 and p < .001, respectively). The C/D ratios of IM (27.78) and PM (35.6) were 13% and 39% higher than those of EM (25.58), respectively. In the pharmacodynamic subgroup analysis, patients in the ineffective LCM group had significantly lower serum concentrations (6.39 ± 3.25 vs. 8.44 ± 3.68 μg/ml, p=.024), whereas patients with adverse events had higher serum concentrations than those without adverse events (11.03 ± 4.32 vs. 7.4 ± 3.1μg/ml, p < .001). Based on this, we suggest a reference range for LCM in the Korean population (6-9μg/ml). Genetic polymorphisms of the CYP2C19 gene affect the serum LCM concentration. Because efficacy and toxicity are apparently related to serum LCM levels, the genetic phenotype of CYP2C19 should be considered when prescribing LCM for patients with epilepsy.

The use of biochemical blood markers for early prediction of the intensity of live weight gain of calves

The aim of the research was to identify promising biochemical markers of blood associated with the intensity of live weight gain in young cattle. The work was carried out in 2021...2022 in the conditions of the dairy farm of LLC Severnaya Niva in the Kortkerossky district of the Komi Republic. A group of newborn heifers of the Kholmogorsky breed (n = 30) was selected for the experiment. It has been established that on the first day after birth, calves with intensive growth rates had lower AsAT activity (r = -0.510) and iron concentration (r = -0.650) in blood serum, and vice versa a higher level of SMLMM рlasma (0.626). At later stages of the analysis, a pronounced correlation of the intensity of body weight gain was observed with respect to the activity of alkaline phosphatase: -0.639 and -0.744 on day 7 and 14, respectively. It was determined that many of the calculated coefficients obtained during the blood test on the 14th day after birth had a more noticeable correlation with the intensity of growth. Such markers included: Alkaline phosphatase/Calcium (-0.746), Alkaline phosphatase/Magnesium (-0.756), Magnesium/Alkaline Phosphatase (-0.760), Calcium×Phosphorus/Alkaline Phosphatase (0.758) and Alkaline Phosphatase/(Calcium+Magnesium) (-0.753). At the next stage, the analysis of the rate of live weight gain in heifers ranked by the increase in the values of the developed coefficients was carried out. It is proved that the use of coefficients contributed to a more pronounced differentiation of the rate of weight gain in comparison with the values established with the use of one alkaline phosphatase. Thus, the calculated index of Alkaline phosphatase/Calcium/ Magnesium on the 1st, 7th and 14th days of postnatal ontogenesis provided a difference between the phenotypes of the 1st and 3rd groups by 74.1(P≤0.05), 92.6 (P≤0.01) and 90.7 (P≤0.001) g of weight gain per day, whereas the difference when using one alkaline phosphatase was 33.3; 16.0 and 12.2 % less. Thus, the use of these coefficients to predict the rate of live weight gain in calves can increase the accuracy of the selection of animals with the desired phenotype in early postnatal ontogenesis.

Danshensu exerts cardioprotective effects in rats with acute myocardial infarction via reduction of infiltration of inflammatory cells and mitigation of myocardial fibrosis

Purpose: To investigate the mitigative impact of danshensu on heart tissues in acute myocardial infarction (AMI) rats, and the mechanism of action involved.&#x0D; Methods: Seventy-five male Sprague-Dawley (SD) rats were used in this study. After successful induction of myocardial infarction, the rats were divided into model group (MG), low-dose danshensu group (LDG; 15 mg/kg), middle-dose danshensu group (MDG; 30 mg/kg), and high-dose danshensu group (HDG; 60 mg/kg), with 15 rats per group. Rats in sham group (SG; n = 15) served as control. Serum levels of biochemical indicators and expressions of various proteins in myocardial tissue were determined using Western blotting, and compared amongst the rat groups.&#x0D; Results: Serum cTnI concentrations in MDG and HDG were significantly decreased, relative to the corresponding concentrations in MDG. There were significantly lower serum concentrations of IL-1 in MDG and HDG than in model rats. Rats in HDG had lower serum IL-6 concentration than MG rats, while TNF-α levels were down-regulated in MDG and HDG, relative to MG (p &lt; 0.05).&#x0D; Conclusion: Danshensu protects the heart function of rats with AMI by decreasing inflammationderived cells and mitigating myocardial fibrosis. Thus, it may be useful in the management of AMI in humans but clinical trials are necessary to ascertain this.&#x0D; Keywords: Danshens; Acute myocardial infarction; Myocardial ischemia-reperfusion; Myocardial fibrosis

A narrative review on the role of carbon nanoparticles in oncology.

The lymphatic system is the first site of metastasis for most tumors and is a common reason for the failure of cancer therapy. The lymphatic system's anatomical properties make it difficult to deliver chemotherapy agents at therapeutic concentrations while avoiding systemic toxicity. Carbon nanoparticles offer a promising alternative for identifying and transporting therapeutic molecules. The larger diameter of lymphatic vessels compared to the diameter of blood vessels, allows carbon nanoparticles to selectively enter the lymphatic system once administered subcutaneously. Carbon nanoparticles stain tumor-draining lymph nodes black following intratumoral injection, making them useful in sentinel lymph node mapping. Drug-loaded carbon nanoparticles allow higher concentrations of chemotherapeutics to accumulate in regional lymph nodes while decreasing plasma drug accumulation. The use of carbon nanoparticles for chemotherapy delivery has been associated with lower mortality, fewer histopathology changes in vital organs, and lower serum concentrations of hepatocellular enzymes. This review will focus on the ability of carbon nanoparticles to target the lymphatics as well as their current and potential applications in sentinel lymph node mapping and oncology treatment regimens. This article is categorized under: Implantable Materials and Surgical Technologies > Nanoscale Tools and Techniques in Surgery.

An Engineered Monovalent Anti-TNF-α Antibody with pH-Sensitive Binding Abrogates Immunogenicity in Mice following a Single Intravenous Dose.

Therapeutic Abs directed toward TNF-α display significant immunogenicity in humans, frequently leading to lower serum concentrations of the Ab that are associated with lower treatment efficacy. The enhanced incidence of immunogenicity observed with this class of therapeutics may be mediated by the expression of TNF-α as a homotrimer, both as a soluble serum protein and as a membrane-associated protein (mTNF-α) on the surface of dendritic cells. The TNF-α homotrimer enables the formation of polyvalent Ab-TNF-α immune complexes (ICs) that enhance binding to FcR and neonatal FcR. Polyvalent ICs and Ab bound to mTNF-α on the surface of dendritic cells can internalize, traffic to the lysosomes, and be processed for presentation by MHC molecules. To diminish immunogenicity caused by trafficking of ICs and mTNF-α to the lysosomes, we engineered a monovalent format of adalimumab with pH-sensitive binding to TNF-α. The engineered variant, termed AF-M2637, did not cross-link TNF-α trimers and consequently formed small, nonprecipitating ICs only. AF-M2637 bound TNF-α with high affinity at pH 7.4 (EC50 = 1.1 nM) and displayed a significantly faster dissociation rate than adalimumab at pH 6.0. No immune response to AF-M2637 was detected in mice following a single i.v. dose. In contrast, rapid immunization was detected following the injection of a single i.v. dose of adalimumab, monovalent adalimumab, or the bivalent form of the pH-sensitive variant. These data suggest that ICs and mTNF-α both contribute to the immunogenicity of adalimumab in mice and provide a general strategy for engineering less immunogenic therapeutic TNF-α Abs.

Effect of calcifediol supplementation on renin-angiotensin-aldosterone system mediators in dogs with chronic kidney disease.

BackgroundChronic kidney disease (CKD) leads to low serum concentrations of vitamin D metabolites. Thus, hypovitaminosis D associated with CKD might contribute to disease progression via increased concentration of renin angiotensin aldosterone system (RAAS) mediators.ObjectivesTo evaluate whether supplementation with calcifediol affects equilibrium concentrations of selected mediators of the RAAS. We hypothesized that vitamin D supplementation will decrease concentration of circulating RAAS mediators in dogs with CKD.AnimalsSix client‐owned adult dogs with IRIS Stage 2 and 3 CKD.MethodsProspective study. Serum 25‐hydroxyvitamin D (25[OH]D), 1,25‐dihydroxyvitamin D (1,25[OH]2D), 24,25‐dihydroxyvitamin D (24,25[OH]2D), RAAS mediators (angiotensin I/II/III/IV/1‐5/1‐7, and aldosterone), and surrogate angiotensin converting enzyme (ACE) activity (calculated by the ratio of angiotensin II to angiotensin I) were evaluated at baseline, after 3 months of calcifediol supplementation, and 2 months after discontinuing administration of supplement.ResultsAll serum vitamin D metabolite concentrations increased significantly by month 3 (P < .001): 25(OH)D (median 250 ng/mL; range, 204‐310), compared to baseline (median 43.2 ng/mL; range, 33.8‐58.3 ng/mL); 1,25(OH)2D (median 66.1 pg/mL; range, 57.3‐88.1 pg/mL) compared to baseline (median 35.2 pg/mL; range, 29.3‐56.7 pg/mL); 24,25(OH)2D (median 68.4 ng/mL; range, 22.1‐142.0 ng/mL) compared to baseline (median 14.4 ng/mL; range, 9.0‐21.3 ng/mL). Calculated ACE activity was significantly lower at month 3 (median 0.5; range, 0.4‐1.0) compared to baseline (median 0.7; range, 0.6‐1.3; P = .01). There were no significant differences in any of the evaluated RAAS variables at any other time‐point.Conclusions and Clinical ImportanceShort‐term calcifediol supplementation in this small group of CKD dogs appeared to decrease ACE activity.

AAV-monoclonal antibody expression protects mice from Ebola virus without impeding the endogenous antibody response to heterologous challenge

Filoviruses cause severe hemorrhagic fever with case fatality rates as high as 90%. Filovirus-specific monoclonal antibodies (mAbs) confer protection in nonhuman primates as late as 5 days after challenge, and FDA-approved mAbs REGN-EB3 and mAb114 have demonstrated efficacy against Ebola virus (EBOV) infection in humans. Vectorized antibody expression mediated by adeno-associated virus (AAV) can generate protective and sustained concentrations of therapeutic mAbs in animal models for a variety of infectious diseases, including EBOV. Here we demonstrate that AAV6.2FF-mediated expression of murine IgG2a EBOV mAbs, 2G4 and 5D2, protects from mouse-adapted (MA)-EBOV infection with none of the surviving mice developing anti-VP40 antibodies above background. Protective serum concentrations of AAV6.2FF-2G4/AAV6.2FF-5D2 did not alter endogenous antibody responses to heterologous virus infection. AAV-mediated expression of EBOV mAbs 100 and 114, and pan-ebolavirus mAbs, FVM04, ADI-15878, and CA45, as human IgG1 antibodies conferred protection against MA-EBOV at low serum concentrations, with minimum protective serum levels as low as 2 μg/mL. Vectorized expression of murine IgG2a or human IgG1 mAbs led to sustained expression in the serum of mice for >400 days or for the lifetime of the animal, respectively. AAV6.2FF-mediated mAb expression offers an alternative to recombinant antibody administration in scenarios where long-term protection is preferable to passive immunization.

Intermittent fasting was superior to a low-fat diet in impacting tumor growth in a pre-clinical model of obesity-driven endometrial cancer (125)

Intermittent fasting was superior to a low-fat diet in impacting tumor growth in a pre-clinical model of obesity-driven endometrial cancer (125)

The serum concentration of brain‑derived neurotrophic factor is lower in ambulatory and clinically stable patients with more advanced systolic heart failure.

Brain‑derived neurotrophic factor (BDNF) is decreased in heart failure (HF), but whether serum BDNF concentration is related to the severity of HF with reduced left ventricular (LV) ejection fraction (LVEF) below 50% is uncertain. We aimed to compare cardiac structure and function in ambulatory and clinically stable patients with HF and LVEF below 50% for lower and higher BDNF serum concentrations. A total of 361 ambulatory patients with a compensated HF and LVEF below 50% underwent cardiac evaluation and measurement of serum BDNF and N‑terminal pro-B‑type natriuretic peptide (NT‑proBNP). Patients from the lower (below median) and higher (equal to or above median) BDNF serum concentration groups were compared by analysis of covariance (ANCOVA) adjusted for age, sex, body mass index, resting heart rate, and systolic blood pressure. The patients were at a median age of 63.8 (interquartile range [IQR], 57.7-71.5) years and had a median LVEF of 31.0% (IQR, 23.0-37.4). Individuals with lower BDNF (<23.5 ng/ml) had significantly (P ≤0.05) more dilated right and left atria both before and after emptying, larger right ventricular end-diastolic diameter, LV end-systolic diameter, lower tricuspid annulus plane systolic excursion, shorter pulmonary acceleration time, higher mitral E to A waves ratio and mitral E wave to tissue Doppler e' wave ratio, and higher concentration of NT‑proBNP. HF patients with LVEF below 50% and lower serum BDNF concentration present more advanced cardiac remodeling and dysfunction than individuals with higher BDNF. Potential mechanisms and clinical consequences of these findings require further investigation.

Effects of Pharmacokinetic Gene Variation on Therapeutic Drug Levels and Antidepressant Treatment Response.

Introduction Pharmacogenetic testing is proposed to minimize adverse effects when considered in combination with pharmacological knowledge of the drug. As yet, limited studies in clinical settings have investigated the predictive value of pharmacokinetic (pk) gene variation on therapeutic drug levels as a probable mechanism of adverse effects, nor considered the combined effect of pk gene variation and drug level on antidepressant treatment response. Methods Two depression cohorts were investigated for the relationship between pk gene variation and antidepressant serum concentrations of amitriptyline, venlafaxine, mirtazapine and quetiapine, as well as treatment response. For the analysis, 519 patients (49% females; 46.6±14.1 years) were included. Results Serum concentration of amitriptyline was associated with CYP2D6 (higher concentrations in poor metabolizers compared to normal metabolizers), of venlafaxine with CYP2C19 (higher concentrations in intermediate metabolizers compared to rapid/ultrarapid metabolizers) and CYP2D6 (lower metabolite-to-parent ratio in poor compared to intermediate and normal metabolizers, and intermediate compared to normal and ultrarapid metabolizers). Pk gene variation did not affect treatment response. Discussion The present data support previous recommendations to reduce starting doses of amitriptyline and to guide dose-adjustments via therapeutic drug monitoring in CYP2D6 poor metabolizers. In addition, we propose including CYP2C19 in routine testing in venlafaxine-treated patients to improve therapy by raising awareness of the risk of low serum concentrations in CYP2C19 rapid/ultrarapid metabolizers. In summary, pk gene variation can predict serum concentrations, and thus the combination of pharmacogenetic testing and therapeutic drug monitoring is a useful tool in a personalized therapy approach for depression.

Maternal serum concentrations of one-carbon metabolism factors modify the association between biomarkers of arsenic methylation efficiency and birth weight

BackgroundInorganic arsenic (iAs) is a ubiquitous metalloid and drinking water contaminant. Prenatal exposure is associated with birth outcomes across multiple studies. During metabolism, iAs is sequentially methylated to mono- and di-methylated arsenical species (MMAs and DMAs) to facilitate whole body clearance. Inefficient methylation (e.g., higher urinary % MMAs) is associated with increased risk of certain iAs-associated diseases. One-carbon metabolism factors influence iAs methylation, modifying toxicity in adults, and warrant further study during the prenatal period. The objective of this study was to evaluate folate, vitamin B12, and homocysteine as modifiers of the relationship between biomarkers of iAs methylation efficiency and birth outcomes.MethodsData from the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort (2011–2012) with maternal urine and cord serum arsenic biomarkers and maternal serum folate, vitamin B12, and homocysteine concentrations were utilized. One-carbon metabolism factors were dichotomized using clinical cutoffs and median splits. Multivariable linear regression models were fit to evaluate associations between each biomarker and birth outcome overall and within levels of one-carbon metabolism factors. Likelihood ratio tests of full and reduced models were used to test the significance of statistical interactions on the additive scale (α = 0.10).ResultsAmong urinary biomarkers, % U-MMAs was most strongly associated with birth weight (β = − 23.09, 95% CI: − 44.54, − 1.64). Larger, more negative mean differences in birth weight were observed among infants born to women who were B12 deficient (β = − 28.69, 95% CI: − 53.97, − 3.42) or experiencing hyperhomocysteinemia (β = − 63.29, 95% CI: − 154.77, 28.19). Generally, mean differences in birth weight were attenuated among infants born to mothers with higher serum concentrations of folate and vitamin B12 (or lower serum concentrations of homocysteine). Effect modification by vitamin B12 and homocysteine was significant on the additive scale for some associations. Results for gestational age were less compelling, with an approximate one-week mean difference associated with C-tAs (β = 0.87, 95% CI: 0, 1.74), but not meaningful otherwise.ConclusionsTissue distributions of iAs and its metabolites (e.g., % MMAs) may vary according to serum concentrations of folate, vitamin B12 and homocysteine during pregnancy. This represents a potential mechanism through which maternal diet may modify the harms of prenatal exposure to iAs.

Effects of Calcium Lactate-Enriched Pumpkin on Calcium Status in Ovariectomized Rats.

This study aimed to evaluate the effects of enriched pumpkin on calcium status in ovariectomized rats. The study was conducted in sixty female Wistar rats, which were divided into six groups: a group fed a standard diet (C) and five ovariectomized groups fed a standard diet (OVX_C) or a diet with calcium lactate (CaL), with calcium lactate-enriched pumpkin (P_CaL), with calcium lactate and alendronate (CaL_B), or with calcium lactate-enriched pumpkin with alendronate (P_CaL_B). After 12 weeks of the intervention, the rats were sacrificed, and their blood and tissues were collected. The calcium concentrations in serum and in tissues were measured using flame atomic absorption spectrometry (AAS). Serum concentrations of procollagen type-1 amino-terminal propeptide (PINP), parathyroid hormone PTH, estrogen (ES), and osteocalcin (OC) were determined with enzyme-linked immunosorbent assay (ELISA). It was found that enriched pumpkin increased the calcium level in the kidneys (194.13 ± 41.01 mg) compared to the C (87.88 ± 12.42 mg) and OVX_C (79.29 ± 7.66 mg) groups. The addition of alendronate increased the calcium level in the femurs (267.63 ± 23.63 mg) and more than six times in the kidneys (541.33 ± 62.91 mg) compared to the OVX_C group (234.53 ± 21.67 mg and 87.88 ± 12.42 mg, respectively). We found that the CaL, P_CaL, and CaL_B groups had significantly lower PINP serum concentrations (4.45 ± 0.82 ng/mL, 4.14 ± 0.69 ng/mL, and 3.77 ± 0.33 ng/mL) and higher PTH serum levels (3.39 ± 0.54 ng/dL, 3.38 ± 0.57 ng/dL, and 3.47 ± 0.28 ng/dL) than the OVX_C group (4.69 ± 0.82 ng/mL and 2.59 ± 0.45 ng/dL, respectively). In conclusion, pumpkin enriched with calcium lactate affects calcium status and normalizes PINP and PTH serum levels in ovariectomized rats. Diet with enriched pumpkin and alendronate increase calcium concentration in the femur. Enriched pumpkin causes calcium to accumulate in the kidneys of ovariectomized rats; alendronate significantly exacerbates this effect.

Maternal Mental Health in Late Pregnancy and Longitudinal Changes in Postpartum Serum Vitamin B-12, Homocysteine, and Milk B-12 Concentration Among Brazilian Women.

BackgroundLittle is known regarding the association between mental health distress during pregnancy and postpartum maternal serum biomarkers of vitamin B-12 status and milk B-12 concentration.ObjectiveTo evaluate the association between depressive and anxiety symptoms in the third trimester of pregnancy and changes in postpartum serum B-12, homocysteine, and B-12 milk concentration.MethodsA total of 101 women (18–40 years) were studied in a prospective cohort with data at the third trimester of pregnancy (baseline) and three postpartum time-points (TPs): 2–8 days (TP1), 28–50 days (TP2), and 88-119 days (TP3) postpartum. B-12 concentrations in milk were measured by competitive chemiluminescent enzyme immunoassay at TP1, TP2, and TP3. Serum B-12 and homocysteine concentrations were evaluated at baseline, TP1, TP2, and TP3 by chemiluminescent immunoassays. Depressive and anxiety symptoms were measured with the Edinburgh Postnatal Depression Scale and the State-Trait Anxiety Inventory at baseline. Spearman's correlation test and multiple linear mixed-effect models were performed.ResultsThe prevalence of depressive and anxiety state symptoms was 35.6 and 39.6% at baseline. High prevalence of low milk B-12 concentration (<310 pmol/L) were observed at TP1 (53.2%), TP2 (71.4%), and TP3 (71.1%). Women with anxiety symptoms at baseline presented higher median concentrations of serum homocysteine at TP1 and lower concentrations of serum and milk B-12 at TP2 compared with women without anxiety symptoms [8 (7; 9) vs. 6 (5; 8) and 266 (188; 369) vs. 332 (272; 413)]. Milk B-12 concentrations were positively and significantly correlated with maternal serum B-12 concentrations at different TP. Women with anxiety symptoms at baseline exhibited a decrease in daily postpartum homocysteine concentrations compared to women without anxiety symptoms (β = −0.002, SE = 0.001, p = 0.024).ConclusionAnxiety symptoms at the end of pregnancy were associated with longitudinal changes in maternal serum homocysteine concentrations during the first 3 months postpartum.

Therapeutic Drug Monitoring for Evaluation of the Efficacy and Safety of Vancomycin in Patients with Orthopaedic Infections

Vancomycin is a drug of choice for the infections caused by methicillin-resistant strains of staphylococci. Its use requires individualised dosing and renal function monitoring.The aim of the study was to evaluate, using therapeutic drug monitoring (TDM), the frequency of reaching target trough serum concentrations (TSCs) and the frequency of renal function impairment in orthopaedic infection patients receiving vancomycin therapy.Materials and methods: the authors carried out a retrospective analysis of vancomycin TSC test results of 457 patients admitted to a purulent osteology department in 2019–2021. The results were grouped according to the number of TSC determination performed as part of TDM (tests 1, 2, and 3). Each of the 3 groups was further divided into 4 subgroups according to the TSCs of vancomycin: ≤9.9 µg/ml (extremely low), 10–14.9 µg/ml (recommended for mild infections), 15–19.9 µg/ml (recommended for bone and joint infections), ≥20 µg/ml (potentially toxic). The results obtained in each group were analysed separately.Results: according to the 1st TDM test, only 9.6% of patients achieved the TSCs of vancomycin recommended for bone and joint infections. Extremely low TSCs, insufficient for treatment of the infections, were found in 64.8% of patients. According to the 2nd and 3rd TSC determinations, dose corrections decreased the percentage of patients with extremely low TSCs to 49.9% and 41.2%, respectively. Potentially toxic TSCs of vancomycin were detected in 48 (10.5%) patients, but renal dysfunction was observed only in 8 (1.75%) of them. The authors exemplify the use of TDM to control the efficacy and safety of vancomycin in patients with pronounced signs of renal function impairment by two clinical cases.Conclusion: with a standard dose of vancomycin, the concentrations recommended for bone and joint infections were reached only in every tenth patient. There was a large percentage of patients with extremely low serum concentrations of the medicinal product (64.8%), but it decreased after dose adjustments. Monitoring of vancomycin concentrations allows for individualised dosing, efficacy control and significant reduction of the risk of adverse kidney reactions.

Early oral feeding after esophagectomy accelerated gut function recovery by regulating brain-gut peptide secretion

BackgroundThe impact of early oral feeding after esophagectomy on brain-gut peptide secretion and gut function recovery has not been well investigated. This study aimed to fill this research gap. MethodsThis study was based on a randomized clinical trial (ClinicalTrials.gov: NCT01998230). The patients in the early oral feeding group started oral food intake on postoperative day 1. In the late oral feeding group, nasogastric/nasoenteral feeding was applied from postoperative day 1 to 7, after which the patients began oral food intake. Serum brain-gut peptides were selected as the primary end points and tested before surgery and on postoperative days 1, 3, and 5. The time to first flatus and first defecation after surgery were evaluated. ResultsA total of 110 participants undergoing minimally invasive McKeown esophagectomy were prospectively included, with 63 patients in the early oral feeding group and 47 patients in the late oral feeding group. The distribution of clinicopathological characteristics was balanced between the 2 groups. Perioperative dynamic surveillance demonstrated higher serum concentrations of excitatory brain-gut peptides (gastrin P = .021, motilin P = .027, and substance-P P = .023) and lower serum concentrations of inhibitory brain-gut peptides (cholecystokinin P = .004 and somatostatin P = .019) in the early oral feeding group. Perioperative serum levels of brain-gut peptides correlated with postoperative early flatus and defecation. The multivariate analysis showed early oral feeding (versus late oral feeding) to be an independent predictive factor for early flatus and defecation (hazard ratio 2.40, P < .001; hazard ratio 2.73, P < .001, respectively). ConclusionThe early oral feeding program may accelerate the recovery of gut function by regulating brain-gut peptide secretion. Brain-gut peptides are possible treatment targets to improve early oral feeding benefits and promote personalized early oral feeding programs.

Relationship between Biomarkers of Carbohydrate, Energy and Adipokine Metabolism in Patients with Acute Myocardial Infarction and Type 2 Diabetes Mellitus

The purpose of the study was to examine the indicators of carbohydrate, energy and adipokine metabolism in acute myocardial infarction patients with or without type 2 diabetes mellitus. Materials and methods. A total of 134 patients with ST-segment elevation acute myocardial infarction in the presence or absence of type 2 diabetes mellitus aged 58.97 ± 7.92 years were examined in the Government Institution “L. T. Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine” and Kharkiv Railway Clinical Hospital No. 1 of the “Center of Healthcare” branch of Public Joint Stock Company “Ukrainian Railway”. The main group (group 1) included 74 patients with acute myocardial infarction and type 2 diabetes mellitus. The comparison group (group 2) was represented by 60 patients with acute myocardial infarction without type 2 diabetes mellitus. The control group was composed of 20 otherwise healthy individuals. Serum concentrations of insulin, adropin, irisin, fatty acid binding protein 4 and C1q/TNF-related protein were measured by enzyme-linked immunosorbent assays. Results and discussion. It was found that the levels of glucose, insulin, HOMA-IR index were increased in acute myocardial infarction patients with or without type 2 diabetes mellitus when compared with the control group (p˂0.05). In acute myocardial infarction patients with type 2 diabetes mellitus, the serum levels of adropin, irisin and C1q/TNF-related protein were significantly lower, while the fatty acid binding protein 4 levels were higher as compared to those in the control group (p&lt;0.05). Acute myocardial infarction patients with type 2 diabetes mellitus demonstrated significantly lower serum concentrations of adropin and C1q/TNF-related protein in comparison with acute myocardial infarction patients without type 2 diabetes mellitus (p&lt;0.05). Negative correlations between blood glucose and adropin (r = -0.499, p&lt;0.001), irisin (r = -0.495, p&lt;0.001), fatty acid binding protein 4 (r = -0.518, p&lt;0.001), between HOMA-IR and adropin (r = -0.304, p&lt;0.02), fatty acid binding protein 4 (r = -0.429, p = 0.001), as well as positive correlations between blood glucose levels and C1q/TNF-related protein (r = 0.435, p = 0.001) were revealed in acute myocardial infarction patients. In acute myocardial infarction patients with type 2 diabetes mellitus, negative correlations were found between blood glucose and adropin (r = -0.504, p&lt;0.001), irisin (r = -0.520, p = 0.03), C1q/TNF-related protein (r = -0.546, p&lt;0.001); between blood insulin and adropin (r = -0.361, p = 0.017), irisin (r = -0.396, p = 0.01), C1q/TNF-related protein (r = -0.361, p = 0.018); between adropin and HOMA-IR (r = -0.508, p = 0.001), C1q/TNF-related protein (r = -0.436, p = 0.003), as well as positive correlation between blood glucose and fatty acid binding protein 4 (r = 0.508, p = 0.007); between blood insulin and fatty acid binding protein 4 (r = 0.501, p = 0.001); between HOMA-IR and fatty acid binding protein 4 (r = 0.516, p&lt;0.001). Conclusion. Characteristics of adropin, irisin, fatty acid binding protein 4 and C1q/TNF-related protein serum levels are evidence of violated energy and adipokine metabolism in both diabetic and non-diabetic patients with acute myocardial infarction. Relationships between adropin, irisin, fatty acid binding protein 4 and C1q/TNF-related protein could indicate involvement of these markers in carbohydrate metabolism

Relation of Serum Micronutrients to Growth and Nutritional Habits of School-Aged Children in Egypt

Proper growth of children depends on several micronutrients. A fundamental role of Zinc and vitamins as A, B12 and D is crucial to prevent a failure to thrive. To study the relationship between Egyptian school aged children growth, nutritional habits and micronutrients deficiencies. Materials and methods: A case control research involved 60 school aged children (age ranged from 6 to 12 years). Group 1 (malnourished) compared with group II (apparently healthy children of matched peers). Serum concentrations of Zinc, Copper, and vitamins as A, B12, and D were measured using ELISA kits. Compared to controls, the cases showed significantly lower serum concentrations of Zinc, vitamin A, B12, and D (P&lt;0.000 in all), while serum concentration of Copper was significantly higher. In the patient's group, serum vitamin B12, and Zinc concentrations showed significant positive correlation with height for age z- score, while serum Copper concentration showed significant negative correlation with BMI for age z- score. Serum Zinc, vitamin B12, and D concentrations were significantly correlated positively with serum vitamin A. Multiple logistic regression showed statistically significant association of high serum Copper and weekly consumption of sweetened beverages among the studied patients (P &lt; 0.01). Vitamins and Zinc deficiencies showed high prevalence among the school children. Serum vitamin B12 and Zinc concentrations showed significant positive correlation with height. The significant association between high serum Copper and sugary beverages among the studied patients may be due to contained preservatives.

Homoarginine treatment of rats improves cardiac function and remodeling in response to pressure overload

Low serum concentrations of the amino acid homoarginine (HA) are associated with increased cardiovascular mortality by incompletely understood mechanisms. This study sought to assess the influence of HA on cardiac remodeling in rats undergoing either transaortic banding or inhibition of nitric oxide synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Male Wistar rats (n= 136) underwent sham operation (SH) or aortic banding (AB). Both groups were equally divided into 14 subgroups, receiving different doses of HA alone or in combination with lisinopril, spironolactone, or L-NAME for 4weeks. HA treatment in AB animals resulted in a dose-dependent improvement of cardiac function up to a concentration of 800 mg·kg-1 ·day-1 . Combining 800 mg·kg-1 ·day-1 HA with spironolactone or lisinopril yielded additional effects, showing a positive correlation with LV ejection fraction (+33%, p= 0.0002) and fractional shortening (+41%, p= 0.0014). An inverse association was observed with collagen area fraction (-41%, p< 0.0001), myocyte cross-sectional area (-22%, p< 0.0001) and the molecular markers atrial natriuretic factor (-74%, p= 0.0091), brain natriuretic peptide (-42%, p =0.0298), beta-myosin heavy chain (-46%, p =0.0411), and collagen type V alpha 1 chain (-73%, p =0.0257) compared to placebo-treated AB animals. Co-administration of HA and L-NAME was found to attenuate cardiac remodeling and prevent NO-deficient hypertension following AB. HA treatment has led to a dose-dependent improvement of myocardial function and marked histological and molecular changes in cardiac remodeling following AB. Combining HA with standard heart failure medication resulted in additional beneficial effects boosting its direct impact on heart failure pathophysiology.

Concentrations of neutrophil gelatinase-associated lipocalin are increased in serum and peritoneal fluid from horses with inflammatory abdominal disease and non-strangulating intestinal infarctions.

Neutrophil gelatinase-associated lipocalin (NGAL) is produced in response to inflammation in horses, but it has not yet been investigated as a biomarker in horses with the abdominal disease. To investigate NGAL in serum and peritoneal fluid in horses with the abdominal disease. Retrospective clinical study. Data from medical records of 270 horses admitted with acute abdominal disease (simple obstructions [n=43], strangulating obstructions [n=104], inflammatory abdominal disease [n=99], non-strangulating intestinal infarction [NSII, n=24]) and 9 healthy control horses were reviewed, and serum and peritoneal fluid samples were retrieved from a biobank. NGAL was measured in serum and peritoneal fluid by ELISA. Differences in NGAL concentrations between groups were assessed. Healthy horses had low serum and peritoneal fluid concentrations of NGAL (median=21.0 and 9.5μg/L, respectively). Neither serum nor peritoneal fluid NGAL concentrations (median serum, peritoneal fluid) differed between healthy horses and horses with simple (28.1μg/L, 13.0μg/L) and strangulating intestinal obstructions (34.7μg/L, 38.4μg/L). Horses with NSII (308.0μg/L, 2163.0μg/L) and inflammatory abdominal disease (171.1μg/L, 314.1μg/L) had higher serum and peritoneal fluid concentrations of NGAL than the other groups (p < 0.001). Peritoneal fluid NGAL concentrations in horses with NSII were higher than in horses with inflammatory abdominal disease (p= 0.03). Retrospective study design; small group of control horses. NGAL is a marker of inflammation in horses with the abdominal disease. The high peritoneal fluid concentration of NGAL in horses with NSII compared to all other groups may render NGAL useful for identifying this condition, which is otherwise difficult to differentiate from other types of peritonitis. Thereby, NGAL may potentially facilitate timely surgical intervention in this group of patients. The results of this study must be evaluated in larger, and preferably prospective, studies to obtain a more comprehensive evaluation of the diagnostic utility of NGAL.

RARE-14. Newborn with hypothalamic hamartoma and Pallister-Hall syndrome

A female full-term newborn of 41 + 2 weeks gestational age with a respiratory adaptation disorder and hypercapnia was transferred from an external maternity clinic to our pediatric intensive care unit. The child is the second child of healthy, non-consanguineous parents. Multiple dysmorphias were noticed at arrival. We identified a choanal atresia/stenosis on both sides in the respiratory tract, a high palate, a submucous cleft palate, a bifid uvula, a laryngeal cleft and a bronchus suis. The child required intubation and ventilation. In addition, we recognized brachydactyly of the hands and feet. The phalanges were not visibly separable. There was nail hypoplasia and rocker bottom feet on both sides. Furthermore, we saw an anal atresia. In routine laboratory work-up, a hypoglycemia and not measurable low TSH serum concentration was noticed. Extended endocrinological laboratory diagnostics revealed a complete pituitary insufficiency. On cranial MRI, a large, iso- to slightly hyperintense space-occupying mass (3.8x3.7x2.5 cm3), originating from the hypothalamus was observed. The brainstem was displaced posteriorly by the mass. The imaging is consistent with a hypothalamic hamartoma. With regard to the present findings, we assumed an underlying genetic cause of the congenital malformations. As a clinical diagnosis, a Pallister-Hall syndrome was suspected. As described in our case, we saw the characteristic features: dysmorphia of the hands and feet, upper respiratory tract, anal atresia, and hypothalamic hamartomas. The Pallister-Hall syndrome is caused by mutations in the GLI3 gene on the 7p13 chromosome. It is inherited in an autosomal dominant manner and its prevalence is unknown. In our patient, a heterozygous, probably pathogenic variant in the GLI3-Gene was proven by Next Generation Sequencing (NGS).