Increase In Excretion Research Articles

Impact of ileal indigestible protein on fecal nitrogen excretion and fecal microbiota may be greater compared with total protein concentration of diets in growing pigs.

In the current study, we hypothesized that an increase in dietary ileal indigestible protein concentration induces an increase in hindgut nitrogen utilization and nitrogen excretion and a shift in fecal microbiota in growing pigs, when compared to pigs given a high total protein diet. Three diets were prepared: 1) standard protein diet based on corn and soybean meal, 2) high-indigestible protein diet in which autoclaved, low-digestible soybean meal replaced soybean meal in the first diet, and 3) high protein diet where the inclusion rate of soybean meal was greater than that of the other diets. The 3 diets were fed to 18 barrows that were fitted with T-cannula at the ileo-cecal junction (initial body weight = 63.4 ± 8.0 kg) in a randomized complete block design with body weight as a blocking factor. Pigs were individually housed in pens and the experiment lasted for 23 d. On days 7 and 21, fecal samples were collected by rectal massage for microbiota analysis. Grab samples of feces were collected on days 20 and 21, and ileal digesta were collected on days 22 and 23 for the determination of energy and nitrogen utilization. Lower apparent ileal digestibility of nitrogen in the high-indigestible protein diet containing autoclaved soybean meal resulted in greater ileal indigestible nitrogen concentration (P < 0.05). Apparent total tract digestibility of nitrogen was lower (P < 0.05), and correspondingly nitrogen concentration and daily fecal nitrogen output were greater (P < 0.05) in the high-indigestible protein diet compared with the other diets. Apparent post-ileal digestibility and hindgut disappearance of nitrogen and gross energy were the greatest (P < 0.05) in the high protein diet, whereas a statistical difference was not observed in those variables between the standard protein diet and the high-indigestible protein diet. Beta diversity metrics of feces in the high-indigestible protein diet on day 21 were different (q < 0.05) from those in the other two diets, which indicates a shift in microbial communities. According to the results of the DESeq2, the direction of microbiota shift induced by the high-indigestible protein diet may have reduced fiber utilization in the hindgut. In conclusion, an increase in dietary ileal indigestible protein concentration increased fecal nitrogen excretion and shifted fecal microbial communities but did not increase nitrogen utilization in the hindgut.

Effects of Low Dietary Cation and Anion Difference on Blood Gas, Renal Electrolyte, and Acid Excretions in Goats in Tropical Conditions.

Goats can suffer from intermittent heat stress in high ambient temperature (HTa) conditions, which causes sporadic respiratory hypocapnia. Obstructive urolithiasis is a common urological problem in goats. Sandy uroliths can be partially relieved by urine acidification with short-term ammonium chloride (NH4Cl) treatment. However, the outcome of urine acidification and the physiological responses to short-term NH4Cl supplementation under respiratory hypocapnia of HTa have rarely been reported. The present study investigated the effect of NH4Cl supplementation that produced a low dietary cation-anion different (l-DCAD) diet on acid-base balance and renal function under HTa conditions. The first experiment investigated the physiological responses to natural HTa to prove whether the peak HTa during the afternoon could induce HTa responses without a change in the plasma cortisol. The partial pressure of CO2 also tended to decrease during the afternoon. The second experiment examined the short-term effect of l-DCAD under HTa conditions. Although the blood pH was within the normal range, there was a clear acid-base response in the direction of metabolic acidosis. The major responses in renal function were an increase in tubular function and acid excretion. With a comparable level of creatinine clearance, the fractional excretions (FE) of chloride and calcium increased, and the FE of potassium decreased. Acid excretion increased significantly in the l-DCAD group. We conclude that under HTa conditions, the tubular excretion of electrolytes and acids was the major response to acid loading without changing the filtration rate. The l-DCAD formulation can be used to acidify urine effectively.

Impact of Albumin Binding Function on Pharmacokinetics and Pharmacodynamics of Furosemide.

Background and Objectives: Albumin binding of the loop diuretic furosemide forms the basis for its transport to the kidney and subsequent tubular secretion, which is a prerequisite for its therapeutic effects. Accordingly, high albumin concentrations should result in higher efficacy of furosemide. However, study results on the combination of furosemide in conjunction with albumin, and on the efficacy of furosemide in hypoalbuminemia, did not confirm this hypothesis. The aim of this study was to determine the efficacy of furosemide not only in relation to albumin concentration, but also taking albumin function into account. Materials and Methods: In a prospective and non-interventional clinical observational trial, blood and urine samples from 50 intensive care patients receiving continuous intravenous furosemide therapy were evaluated. Albumin binding capacity (ABiC) determination allowed conclusions to be drawn about the binding site-specific loading state of albumin, by quantifying the unbound fraction of the fluorescent marker dansylsarcosine. In addition, assessment of the total concentration of furosemide in plasma and urine, as well as the concentration of free furosemide fraction in plasma, was performed by HPLC-MS. The efficacy of furosemide was evaluated by the ratio of urine excretion to fluid intake. Results: In patients with an ABiC ≥ 60% free furosemide fraction was significantly lower compared to patients with a lower ABiC (p &lt; 0.001), urinary furosemide concentration was higher (p = 0.136), and a significantly higher proportion of infused furosemide was excreted renally (p = 0.010). ABiC was positively correlated (r = 0.908, p = 0.017) with increase in the urine excretion to fluid input ratio after initiation of furosemide therapy. Conclusions: ABiC could serve as a marker for individual response to furosemide and could be used to generate patient-specific therapeutic regimens. In view of the relatively low number of patients in this study, the relationship between furosemide efficacy and albumin function should be investigated in larger studies in the future.

In the Limelight: December 2022

In the Limelight: December 2022

Angiotensin II Modulates Calcium/Phosphate Excretion in Experimental Model of Hypertension: Focus on Bone.

A link between hypertension and long-term bone health has been suggested. The aim of this study was to investigate the effects of chronic angiotensin II administration on urinary calcium/phosphate excretion, bone mineral density, bone remodeling and osteoblast population in a well-established experimental model of hypertension, in the absence of possible confounding factors that could affect bone metabolism. Male Sprague-Dawley rats, divided in the following groups: (a) Angiotensin II (Ang II, 200 ng/kg/min, osmotic minipumps, sub cutis, n = 8); (b) Ang II+losartan (Los, 50 mg/kg/day, per os, n = 6); (c) control group (physiological saline, sub cutis, n = 9); and (d) control+losartan (n = 6) were treated for four weeks. During the experimental period, 24-hour diuresis, urinary calcium, phosphate and sodium excretion were measured prior to the treatment, at two weeks of treatment, and at the end of the treatment. Systolic blood pressure was measured by plethysmography technique (tail cuff method). At the end of the experimental protocol, the rats were euthanized and peripheral quantitative computed tomography at the proximal metaphysis and at the diaphysis of the tibiae and quantitative bone histomorphometry on distal femora were performed. Angiotensin II-dependent hypertension is associated with increased calcium and phosphate excretion. AT1 receptor blockade prevented the increase of blood pressure and phosphate excretion but did not affect the increase of calcium excretion. These changes took place without significantly affecting bone density, bone histology or osteoblast population. In conclusion, in our experimental conditions, angiotensin II-dependent hypertension gave rise to an increased urinary excretion of calcium and phosphate without affecting bone density.

Assessment of the Exposure to Aromatic Amines in Users of Various Tobacco/Nicotine Products.

Aromatic amines such as ortho-toluidine (o-Tol), 2-aminonaphthalene (2-AN), and 4-aminobiphenyl (4-ABP) are human bladder carcinogens and occur at various workplaces, in ambient air, in food products, as well as in tobacco smoke. In a clinical study comprising a period of 74 h under confinement, we investigated the exposure to these three aromatic amines as well as to 3-aminobiphenyl (3-ABP) by measuring them in urine of habitual users of combustible cigarettes (CCs), electronic cigarettes (ECs), heated tobacco products (HTPs), oral tobacco (OT), and nicotine replacement therapy products (NRTs). Non-users (NU) of any tobacco/nicotine products served as (negative) control group. Smokers (CC) exhibited the highest levels for all four aromatic amines measured, significantly elevated compared to NU and non-CC users. Urinary levels in users of EC, HTP, NRT (mostly nicotine gum), and OT (mostly snus) were not significantly different from those in NU. Users of HTP showed slightly elevated urinary excretion levels of o-Tol, 3-ABP, and 4-ABP compared to some other non-CC groups. Dose markers such as daily consumption, urinary nicotine equivalents (Nequ), and plasma cotinine (CotP) were found to be consistently and significantly correlated with the excretion of aromatic amines for smokers (CC) only. Excretion levels of 3- and 4-ABP in smokers were significantly lower in the urine collected overnight compared to that collected during the day, which is just the opposite of what we observed for other biomarkers in this study. The possible reason for this observation is discussed. In conclusion, in contrast to smoking of CCs, the use of ECs, HTPs, nicotine gum, and oral tobacco was not observed to be associated with significant exposure to the aromatic amines o-Tol, 2-AN, 3-ABP, and 4-ABP. The observed slight increase in o-Tol, 3-ABP, and 4-ABP excretions in HTP users has to be verified in larger studies.

OR29-2 Comprehensive Steroid and Global Metabolome Analysis by Mass Spectrometry and Machine Learning to Understand Metabolic Risk in Benign Adrenal Tumours With Mild Autonomous Cortisol Secretion

Abstract Background Benign adrenal tumours are found in 3-10% of adults and can be non-functioning (NFAT) or associated with adrenal hormone excess. Analysing 1305 prospectively recruited patients with benign adrenal tumours, we recently demonstrated that 45% of patients had mild autonomous cortisol secretion (MACS), i.e. biochemical evidence of cortisol excess without distinct signs of Cushing syndrome (CS). We found that MACS increases the prevalence and severity of type 2 diabetes and hypertension and primarily affects women (Ann Int Med. 2022 Doi: 10.7326/M21-1737). Here we analysed the cohort's steroid metabolome and non-targeted global metabolome to reveal underlying metabolic processes. Methods We analysed 24-h urine samples from 1305 patients (649 NFAT, 591 MACS, 65 CS) using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) multi-steroid profiling assay. In addition, we performed non-targeted serum metabolome analysis in a representative sub-cohort (104 NFAT, 140 MACS, 47 CS) employing two complementary LC-MS assays, HILIC and C18-lipidomics. The steroid and global metabolome data were analysed by two supervised machine learning approaches, generalized matrix learning vector quantization and ordinal regression, to identify the most relevant metabolic changes. Findings Urine steroid metabolome analysis revealed an increase in glucocorticoid excretion from NFAT over MACS to CS, whereas androgen excretion decreased. Increased glucocorticoid metabolites were also the major differentiators between MACS patients with and without type 2 diabetes and hypertension, respectively. Lipidome analysis by machine learning identified glycerophospholipids, lysoglycerophospholipids, triacylglycerides, ceramides, sphingolipids, and acylcarnitines as the most relevant metabolite classes exhibiting gradually progressive changes with increasing cortisol excess (NFATInterpretation: We show a gradual change in the lipidome towards lipotoxicity with increasing cortisol excess. MACS patients with type 2 diabetes and hypertension had higher glucocorticoid output than other MACS patients, suggestive of a causative contribution of cortisol excess to their increased cardiometabolic burden. Observed changes may hold promise for risk stratification in MACS, a highly relevant and previously largely overlooked metabolic risk condition. Presentation: Tuesday, June 14, 2022 10:00 a.m. - 10:15 a.m.

Diabetic Nephropathy: Pathogenesis to Cure.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disorder (ESRD). It is defined as the increase in urinary albumin excretion (UAE) when no other renal disease is present. DN is categorized into microalbuminuria and macroalbuminuria. Factors like high blood pressure, high blood sugar levels, genetics, oxidative stress, hemodynamic and metabolic changes affect DN. Hyperglycemia causes renal damage through activating protein kinase C (PKC), producing advanced end glycation products (AGEs) and reactive oxygen species (ROS). Growth factors, chemokines, cell adhesion molecules, inflammatory cytokines are found to be elevated in the renal tissues of the diabetic patient. Many different and new diagnostic methods and treatment options are available due to the increase in research efforts and progression in medical science. However, until now, no permanent cure is available. This article aims to explore the mechanism, diagnosis, and therapeutic strategies in current use for increasing the understanding of DN.

ODP007 Nephron Specific ATP6AP2 Knockout Increases Urinary Excretion of Fatty Acids while Decreasing Renal Cortical Megalin Expression

Abstract We recently reported that mice with inducible nephron specific knockout of ATP6AP2 are resistant to diet induced obesity while demonstrating significant increases in urine glucose and albumin excretion. It is not known whether urinary loss of other metabolites such as lipids contributes to impaired weight gain in this model. Nonesterified fatty acids (NEFA) are filtered by the glomerulus bound to albumin and are normally reabsorbed in the proximal tubule via the megalin-cubulin complex. We hypothesized that nephron specific ATP6AP2 knockout reduces megalin expression leading to increased urinary NEFA excretion. Eight-week-old male inducible nephron specific ATP6AP2 knockout mice underwent either induction with oral doxycycline or received sucrose water as controls before being placed on either normal diet (ND) or high fat diet (HFD) for 6 months. At the end of this period, organic lipid extraction was performed on 24-hour urine samples to determine 24-hour NEFA excretion. RT-PCR was utilized to determine renal cortical expression of LRP2, the gene for megalin. Similar to prior reports, HFD alone increased body weight by 76% at 6 months compared to ND controls (p&amp;lt;0. 01) while HFD fed knockout mice had 53% lower body weight than HFD controls (p&amp;lt;0. 01). There was no significant change in 24-hour NEFA excretion between ND and HFD controls, but knockout mice on ND had 79% greater 24-hour urine NEFA excretion than ND controls while HFD fed knockout mice had 142% greater 24-hour NEFA excretion compared to HFD controls (p&amp;lt;0. 05). RT-PCR for renal cortical expression of LRP2, the gene for megalin, revealed 55% and 76% reduction in expression in ND and HFD fed knockout mice respectively compared to their respective ND and HFD fed controls (p&amp;lt;0. 01). These results indicate that nephron ATP6AP2 knockout results in increased urinary NEFA excretion via decreased megalin expression in the renal cortex. Further investigation is warranted into how ATP6AP2 may regulate the activity of the megalin-cubulin complex and what effects this may have on lipid reabsorption by the kidney. Presentation: No date and time listed

Сomprehensive restorative treatment of posture disorders in children with connective tissue dysplasia

Aim is to develop a comprehensive program of restorative treatment of posture disorders in children against the background of connective tissue dysplasia. Materials and methods. Ninety children aged from 4 to 17 years were under observation. Of these, 60 patients with connective tissue dysplasia (CTD) were divided into an experimental group (30 children) and a comparison group (30 children). These CTD children were under medical supervision from 2010 to 2020. The reference group consisted of 30 conditionally healthy children of the same age. All children were comprehensively examined. All СTD patients during the entire period of dispensary observation underwent comprehensive restorative treatment using methods of physical therapy, swimming and teaching patients at the educational school “Posture Correction” for children. The data obtained were processed statistically. Results. Characteristic signs of hereditary disorders of connective tissue development were revealed in all CTD children. An increase in the concentration of oxyproline in the blood serum and an increase in urinary excretion of oxyproline and calcium were found. After 5 years from the start of rehabilitation measures, there was an increase in endurance of the back muscles, a minimum number of pathological manifestations, including arthritis, arthralgic syndromes, coccygodynia. Ten years later, at the age of 14 years, the children of the experimental group formed a good posture, a well-off muscular corset and a minimal number of complications. Patients of the comparison group during the observation process more often complained of a feeling of fatigue, prolonged, incurable pain in the thoracic and lumbar spine, weak muscle corset. Conclusion. If CTD signs are detected in children, long-term dispensary observation should be carried out in outpatient conditions with the inclusion of a set of exercises of physical therapy and other rehabilitation measures. With the initial CTD manifestations on the part of the spine, children should be recommended to use a back support or a semi-rigid corset for the duration of increased loads, lessons, and long training sessions.

ВЛИЯНИЕ ТОРАСЕМИДА И ИНДАПАМИДА НА ЭКСКРЕЦИЮ МАГНИЯ, КАЛИЯ, КАЛЬЦИЯ И НАТРИЯ У ЖЕНЩИН ПОСТМЕНОПАУЗАЛЬНОГО ВОЗРАСТА С АРТЕРИАЛЬНОЙ ГИПЕРТЕНЗИЕЙ И ХРОНИЧЕСКОЙ СЕРДЕЧНОЙ НЕДОСТАТОЧНОСТЬЮ В ЗАВИСИМОСТИ ОТ НАЛИЧИЯ ДЕФИЦИТА МАГНИЯ

The aim of study was to assess torasemide and indapamide effects on magnesium (Mg), potassium (K), calcium (Ca), and sodium (Na) excretion in postmenopausal women with hypertension and heart failure with preserved ejection fraction (HFpEF) depending on Mg exchange. Material and methods. 140 postmenopausal women with hypertension and HFpEF were examined. Based on Mg-tolerance test results, patients were divided into 2 groups: with (n = 72) and without Mg deficiency (n = 68) with randomization into 4 subgroups: 1a, 1b – 36 patients and 2a, 2b - 34 women in each. Subgroups 1a and 2a received torasemide 5 mg, 1b and 2b – indapamide 2.5 mg. Daily diuresis, Na, K, Ca and Mg excretion were determined before and after diuretics use. Results. Diuretics caused equal (p&gt;0.05) increase (p&lt;0.001) in daily urine output and natriuresis by 561 (95%CI: 556–571) ml and 71.0 (95%CI: 68.9– 73.1) mmol/24h. K excretion increased (p&lt;0.0001) only with indapamide use by 21.1 (95% CI: 18.4-23.8) mmol / 24h and 22.3 (95% CI: 19.5-25.0) mmol / 24h in groups 1b and 2b. Mg excretion increase was not detected (p&gt;0.05) only in patients with Mg deficiency torasemide subgroup, but Ca loss remained unchanged (p&gt;0.05) in indapamide subgroups. K/Na and Ca/Na ratio decreased in all groups, while Mg/Na increased with indapamide use and decreased with torasemide use. Torasemide decreased (p&lt;0.001) Mg/Ca excretion ratio, but indapamide decreased (p&lt;0,0001) the one. Conclusion. Indapamide caused significant increase in K, Mg excretion and Mg/Ca, while torasemide increased Ca loss, decreased Mg/Ca, and did not affect K loss in postmenopausal women with hypertension, HFpEF regardless to Mg deficiency. Torasemide did not lead to Mg losses increase in macronutrient-deficiency patients.

Acute kidney injury and diabetic kidney disease in children with acute complications of diabetes

BackgroundDiabetic ketoacidosis (DKA) and hyperglycaemia without ketoacidosis are common acute complications of diabetes. Their association with acute kidney injury (AKI) and diabetic kidney disease (DKD) was studied.MethodsThe study group consisted of 197 children with type 1 diabetes with average diabetes duration of 8.08 ± 2.32 years. The medical history of the patients was retrospectively reviewed. The number of children with severe hyperglycaemia, DKA and AKI was assessed. The association with the risk of chronic kidney disease (CKD) was analysed.ResultsAKI was found in 14% of cases hospitalised for DKA and 8% of cases hospitalised for hyperglycaemia. Patients with AKI showed a significantly increased corrected sodium (141.23 ± 5.09 mmol/L, p = 0.035). Patients with AKI in DKA showed a significant increase in WBC (20.73 ± 8.71 × 103/µL, p = 0.0009). Follow-up analysis after a minimum of 5 years of diabetes revealed that a single episode of DKA was found in 63 patients and a single episode of AKI in 18 patients. Two or more episodes of DKA were found in 18 patients, and nine cases were complicated by AKI. These patients showed a significant increase in urinary albumin excretion (44.20 ± 64.21 mg/24 h), the highest values of eGFR and the worst glycaemic control.ConclusionsDiabetic children can develop AKI in the course of DKA and hyperglycaemia without ketoacidosis, which is associated with volume depletion and reflected by corrected sodium concentration. AKI in DKA seems to be complicated by stress and inflammation activation. AKI and poor glycaemic control with repeated DKA episodes can magnify the risk of progression to DKD.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Infusion of an acidified ethanolic-dextrose solution enhances urinary ammonium excretion and increases acid resilience in non-mechanically ventilated acidotic rabbits.

Hitherto, the rabbit has long been known to have a very poor tolerance to non—volatile acid. In this study, we tested the hypothesis that acid resilience in the acidotic rabbit can be increased by enhancing the plasma availability of a naturally occurring volatile fatty acid, namely acetate. To ascertain the relative merits of the respiratory and renal systems in contributing to that resilience, we conducted our studies in non—ventilated and mechanically ventilated acidotic animals. Using ethanol as a feeder of acetate, and to counteract the antidiuretic effects of surgical interventions, we induced acidosis in anaesthetised rabbits, by intravenously infusing an acidified ethanolic dextrose solution. We observed very potent respiratory regulation of arterial blood pH coupled with a notable renal response by way of a 25-fold increase in urinary ammonium excretion in the non—ventilated group. In contrast, arterial blood pH plummeted much more rapidly in the mechanically—ventilated animals, but the compensated renal response was enormous, in the form of an 85 -fold increase in urinary ammonium output. Despite this significant adaptive renal response, the non -mechanically ventilated group of rabbits showed the greater acid resilience. This was attributed to an acetate stimulated flux through a series of metabolic pathways, generating supplementary buffer in the form of bicarbonate and ammonia, complemented by a robust respiratory response.

The New Nordic Renal Diet Induces a Pronounced Reduction of Urine Acid Excretion and Uremic Toxins in Chronic Kidney Disease Patients (Stage 3 and 4)

Metabolic acidosis and the uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are associated with increased risks of kidney disease progression, muscle catabolism, cardiovascular disease, and mortality in patients with chronic kidney disease (CKD). The New Nordic Renal Diet (NNRD) is a plant-focused meal pattern, with reduced phosphorus and protein content compared to an average Danish diet. Due to a higher amount of plant-based products, we hypothesized that NNRD would reduce renal excretion of acids and uremic toxins. Thus, we evaluated the effects of NNRD on metabolic acidosis and uremic toxins in patients with moderate CKD, stages 3-4. This post hoc analysis is based on a randomized controlled crossover trial comparing 1 week of the NNRD to a control 1-week period of an average Danish diet, in patients with CKD stages 3 and 4. Urine pH and urine excretion of bicarbonate, ammonium, titratable acids, IS, and PCS alongside plasma total CO2 (tCO2) were measured at days 1, 4, and 7 in 18 patients. After 7days on NNRD 24-hour urine net acid excretion was decreased by 80% (P<.001), 24-hour urine excretion of ammonium and bicarbonate decreased by 34% (P<.001), and increased by 678% (P<.001), respectively, compared with the control period. Plasma tCO2 was increased by 8% (P=.005). Moreover, 24-hour urine excretion of PCS and IS were reduced by 31% (P=.018) and 29% (P<.001), respectively. One week of NNRD in patients suffering from moderate CKD effectively improved metabolic acidosis with a marked reduction in urine net acid excretion that included a large increase in urine bicarbonate excretion. In addition, NNRD reduced urinary excretion of the uremic toxins PCS and IS. These results encourage further investigations of the long-term effects of NNRD on renal protection in patients with CKD.

Totum-070 prevents diet-induced hypercholesterolemia in western diet fed mice and inhibits cholesterol uptake in human enterocyte caco2 cell line

Abstract Introduction It is well known that hypercholesterolemia is an important modifiable risk factor in the development of cardiovascular diseases. Lowering blood cholesterol level reduces the incidence of atherosclerotic disease. Totum-070 (T070) is a clinical stage polyphenol-rich active substance composed by the association of 5 plant extracts. Purpose We assessed the hypothesis that administration of T070 prevents hypercholesterolemia in western diet fed mice and explored the potential mechanisms involved in vitro in human enterocytes. Methods C57BL/6 mice were fed either a normal diet (ND) or western diet (WD) for 6 weeks and received either vehicle or T070 (1mg/kg or 3mg/kg) daily by gavage (n=14 mice per group). Food intake, body weight and plasma lipid were monitored along study duration. Liver and feces lipid content were quantified at the end of the study. For in vitro studies, human Caco2 cells were differentiated in transwells for 21 days. To perform cholesterol uptake assay, [1,2-3H(N)]-cholesterol was incubated in apical medium for 1 hour in presence or not of T070 prior to quantification of radioactivity in the cells. Results In mice, supplementation with T070 had no effect on food intake during the study. At the end of the in vivo study, body weight in WD-fed mice was increased to 28.3±0.8 g compared to the ND group (24.5±0.4 g, p&amp;lt;0.001). Interestingly, a significant (p&amp;lt;0.01) 29% reduction in body weight gain was observed in the T070 3mg/kg group compared to the WD group at the end of the study. Compared to WD group, total-cholesterol in mice supplemented by T070 was reduced in a dose dependent manner (298±8 mg/dl WD vs 276±9 mg/dl T070 1mg/kg, p=0.19, and 265±8 mg/dl T070 3mg/kg, p&amp;lt;0.05). Furthermore, hepatic steatosis induced by the WD was reduced by 73% (p&amp;lt;0.001) in the T070 3mg/kg group. Hepatic and intestinal gene expression were drastically altered by WD feeding compared to ND, while supplementation with T070 tended to restore normal expression levels for many genes implicated in lipid and lipoprotein metabolism. A significant increase in fecal cholesterol excretion was observed in mice supplemented with T070 3 mg/g compared to the mice fed with WD alone (442.3±151.7 nmol/day WD + T070 3mg/g vs 75.4±5.9 nmol/day WD, p&amp;lt;0.05). Studies in human enterocytes demonstrated that 1 g/l T070 reduced cholesterol uptake by 35% (p&amp;lt;0.001), suggesting that T070 inhibits intestinal cholesterol absorption. Conclusion Our results show the beneficial effect of supplementation with Totum-070 to prevent induction of hypercholesterolemia in a nutritional mouse model. Investigation of mechanisms of action in enterocytes demonstrate the role of Totum-070 to inhibit intestinal cholesterol absorption. These results highlight the interest of using Totum-070 for the management of hypercholesterolemia. Funding Acknowledgement Type of funding sources: None.

A follow-up study on workers involved in the graphene production process after the introduction of exposure mitigation measures: evaluation of genotoxic and oxidative effects

During nanomaterial (NM) production, workers could be exposed, particularly by inhalation, to NMs and other chemicals used in the synthesis process, so it is important to have suitable biomarkers to monitor potential toxic effects. Aim of this study was to evaluate the effectiveness of the introduction of exposure mitigation measures on workers unintentionally exposed to graphene co-pollutants during production process monitoring the presumable reduction of workplace NM contamination and of early genotoxic and oxidative effects previously found on these workers. We used Buccal Micronucleus Cytome (BMCyt) assay and Fpg-comet test, resulted the most sensitive biomarkers on our first biomonitoring work, to measure the genotoxic effects. We also detected urinary oxidized nucleic acid bases 8-oxoGua, 8-oxoGuo and 8-oxodGuo to evaluate oxidative damage. The genotoxic and oxidative effects were assessed on the same graphene workers (N = 6) previously studied, comparing the results with those found in the first biomonitoring and with the control group (N = 11). This was achieved 6 months after the installation of a special filter hood (where to perform the phases at higher risk of NM emission) and the improvement of environmental and personal protective equipment. Particle number concentration decreased after the mitigation measures. We observed reduction of Micronucleus (MN) frequency and oxidative DNA damage and increase of 8-oxodGuo excretion compared to the first biomonitoring. These results, although limited by the small subject number, showed the efficacy of adopted exposure mitigation measures and the suitability of used sensitive and noninvasive biomarkers to bio-monitor over time workers involved in graphene production process.

Comprehensive and Safe Decongestion in Acutely Decompensated Heart Failure.

Progressive intravascular, interstitial, and alveolar fluid overload underlies the transition from compensated to acutely decompensated heart failure and loop diuretics are the mainstay of treatment. Adverse effects and resistance to loop diuretics received much attention while the contribution of a depressed cardiac output to diuretic resistance was downplayed. Analysis of experience with positive inotropic agents, especially dobutamine, indicates that enhancement of cardiac output is not consistently associated with increased renal blood flow. However, urinary output and renal sodium excretion increase likely due to dobutamine-mediated decrease in renal and systemic reduced activation of sympathetic nervous- and renin-angiotensin-aldosterone system. Mechanical circulatory support with left ventricular assist devices ascertained the contribution of low cardiac output to diuretic resistance and the pathogenesis and progression of kidney disease in acutely decompensated heart failure. Diuretic resistance commonly occurs in acutely decompensated heart failure. However, failure to resolve fluid overload despite high doses of loop diuretics should alert to the presence of a low cardiac output state.

Effect of guanidinoacetic acid supplementation on nitrogen retention and methionine methyl group flux in growing steers fed corn-based diets.

Six ruminally cannulated Holstein steers (256 ± 14 kg) were used in a 6 × 6 Latin square design to assess effects of guanidinoacetic acid (GAA) supplementation on N retention and methionine (Met) methyl group flux in growing cattle fed corn-based diets. Factorial treatments were two levels of Met (0 or 5 g/d) and three levels of GAA (0, 7.5, or 15 g/d) delivered by continuous abomasal infusion. Periods were 10 d in length and included 6 d of treatment adaptation, 3 d for total fecal and urine collections, and 1 d for blood sampling and flux measurements. Urinary N linearly increased (P < 0.01) with GAA supplementation and decreased (P < 0.05) with Met supplementation. Fecal N excretion was unaffected (P ≥ 0.42) by treatment. Retained N was not affected by GAA supplementation, but it was increased (P < 0.01) by Met supplementation. Use of methionine for transmethylation reactions, as well remethylation of homocysteine, was not affected by GAA supplementation when Met was not supplemented, but tended to be linearly increased by GAA supplementation when Met was supplemented (GAA-linear × Met interaction; P = 0.07), with the increases matching the amount of GAA provided. This response suggests that methylation reactions for compounds other than GAA were reduced by GAA supplementation when Met supply was deficient. Plasma concentrations and urinary excretion of creatine increased linearly (P = 0.03 and P = 0.06, respectively) when GAA was supplemented. There was a linear increase (P < 0.01) in urinary GAA excretion with GAA supplementation. Neither plasma concentration nor urinary excretion of creatinine was affected (P ≥ 0.17) by treatment. No treatment differences (P ≥ 0.13) were observed for plasma haptoglobin concentrations. Plasma urea-N linearly increased (P < 0.05) with GAA supplementation. Concentrations of Met and taurine increased (P < 0.05) when Met was supplemented. Plasma arginine was greatest at the intermediate level of supplemental GAA (quadratic, P < 0.05). The increase in N retention when Met was supplemented demonstrates Met was limiting in the corn-based diet. Supplementation of GAA alone or with Met as a methyl donor did not increase N retention in growing steers, perhaps because creatine production was favored over protein deposition as a use for Met.

Nicotinamide mononucleotide ameliorates adriamycin-induced renal damage by epigenetically suppressing the NMN/NAD consumers mediated by Twist2

The activation of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, Sirt1, after the administration of nicotinamide mononucleotide (NMN) suppresses many diseases. However, the role of NMN and Sirt1 in focal glomerulosclerosis (FSGS) has not yet been elucidated. This study aimed to assess the protective effect of NMN treatment in mice with adriamycin (ADR)-induced FSGS. Transient short-term NMN treatment was administered to 8-week-old ADR- or saline-treated BALB/c mice (Cont group) for 14 consecutive days. NMN alleviated the increase in urinary albumin excretion in the ADR-treated mice. NMN treatment mitigated glomerulosclerosis and ameliorated the reduced Sirt1 expression and elevated Claudin-1 expression in the kidneys of the mice. Moreover, this treatment improved the decrease in histone methylation and the expression level of Dnmt1 and increased the concentration of NAD+ in the kidney. Dnmt1 epigenetically suppressed the expression of the NMN-consuming enzyme nicotinamide mononucleotide adenyltransferase1 (Nmnat1) by methylating the E-box in the promoter region and repressing the NAD-consuming enzyme PARP1. Additionally, NMN downregulated the expression of Nmnat1 in the ADR-treated mice. Short-term NMN treatment in FSGS has epigenetic renal protective effects through the upregulation of Sirt1 and suppression of the NAD and NMN consumers. The present study presents a novel treatment paradigm for FSGS.

Levels of donor-derived cell-free DNA and chemokines in BK polyomavirus-associated nephropathy.

BK polyomavirus-associated nephropathy (BKPyVAN) carries a risk of irreversible allograft injury. While detection of BK viremia and biopsy assessment are the current diagnostic gold standard, the diagnostic value of biomarkers reflecting tissue injury (donor-derived cell-free DNA [dd-cfDNA]) or immune activation (C-X-C motif chemokine ligand [CXCL]9 and CXCL10) remains poorly defined. For this retrospective study, 19 cases ofBKPyVANwere selected from the Vienna transplant cohort (biopsies performed between 2012 and 2019). Eight patients with T cell-mediated rejection (TCMR), 17 with antibody-mediated rejection (ABMR) and 10 patients without polyomavirus nephropathy or rejection served as controls. Fractions of dd-cfDNAwere quantified using next-generation sequencing and CXCL9 and CXCL10 were detected using multiplex immunoassays. BKPyVANwas associated with a slight increase in dd-cfDNA(median; interquartile range: .38% [.27%-1.2%] vs. .21% [.12%-.34%] in non-rejecting control patients; p=.005). Levels were far lower than in ABMR (1.2% [.82%-2.5%]; p=.004]), but not different from TCMR (.54% [.26%-3.56%]; p=.52). Within theBKPyVANcohort, we found no relationship between dd-cfDNAlevels and the extent of tubulo-interstitial infiltrates,BKPyVANclass and BK viremia/viruria, respectively. In some contrast to dd-cfDNA, concentrations of urinary CXCL9 and CXCL10 exceeded those detected in ABMR, but similar increases were also found in TCMR. BKPyVANcan induce moderate increases in dd-cfDNAand concomitant high urinary excretion of chemokines, but this pattern may be indistinguishable from that of TCMR. Our results argue against a significant value of these biomarkers to reliably distinguishBKPyVANfrom rejection.