Creatine Levels Research Articles

Metabolomics profile in acute respiratory distress syndrome by nuclear magnetic resonance spectroscopy in patients with community-acquired pneumonia

BackgroundAcute respiratory distress syndrome (ARDS) is a challenging clinical problem. Discovering the potential metabolic alterations underlying the ARDS is important to identify novel therapeutic target and improve the prognosis. Serum and urine metabolites can reflect systemic and local changes and could help understanding metabolic characterization of community-acquired pneumonia (CAP) with ARDS.MethodsClinical data of patients with suspected CAP at the First Affiliated Hospital of Wenzhou Medical University were collected from May 2020 to February 2021. Consecutive patients with CAP were enrolled and divided into two groups: CAP with and without ARDS groups. 1H nuclear magnetic resonance-based metabolomics analyses of serum and urine samples were performed before and after treatment in CAP with ARDS (n = 43) and CAP without ARDS (n = 45) groups. Differences metabolites were identifed in CAP with ARDS. Furthermore, the receiver operating characteristic (ROC) curve was utilized to identify panels of significant metabolites for evaluating therapeutic effects on CAP with ARDS. The correlation heatmap was analyzed to further display the relationship between metabolites and clinical characteristics.ResultsA total of 20 and 42 metabolites were identified in the serum and urine samples, respectively. Serum metabolic changes were mainly involved in energy, lipid, and amino acid metabolisms, while urine metabolic changes were mainly involved in energy metabolism. Elevated levels of serum 3-hydroxybutyrate, lactate, acetone, acetoacetate, and decreased levels of serum leucine, choline, and urine creatine and creatinine were detected in CAP with ARDS relative to CAP without ARDS. Serum metabolites 3-hydroxybutyrate, acetone, acetoacetate, citrate, choline and urine metabolite 1-methylnicotinamide were identified as a potential biomarkers for assessing therapeutic effects on CAP with ARDS, and with AUCs of 0.866 and 0.795, respectively. Moreover, the ROC curve analysis revealed that combined characteristic serum and urine metabolites exhibited a better classification system for assessing therapeutic effects on CAP with ARDS, with a AUC value of 0.952. In addition, differential metabolites strongly correlated with clinical parameters in patients with CAP with ARDS.ConclusionsSerum- and urine-based metabolomics analyses identified characteristic metabolic alterations in CAP with ARDS and might provide promising circulatory markers for evaluating therapeutic effects on CAP with ARDS.

ANALISIS SURVIVAL PENDERITA GAGAL GINJAL DENGAN PENDEKATAN MULTIVARIATE ADAPTIVE REGRESSION SPLINE

Survival analysis is a statistical method where the outcome variable that is considered is the time until the occurrence of an event or called an event. Survival analysis in the medical world can be used to test the survival of patients suffering from a disease, one of which is kidney failure. Based on the results of the 2013 Basic Health Research, 0.2% of the total population of Indonesia, namely 499,800 people, experienced kidney failure. Kidney failure is a process of decreasing kidney function that requires renal replacement therapy, in the form of hemodialysis or kidney transplantation. If the survival data involve independent variables that are thought to affect the survival time, then the Cox Proportional Hazard (PH) regression approach can be developed which can be developed for the Multivariate Adaptive Regression Spline (MARS) approach. The MARS approach is a nonparametric regression approach with high-dimensional data, namely data with an independent variable of 3≤𝑝≤20 and a data sample of 50≤N≤1000. This study aims to describe the characteristics of patients with kidney failure, identify the factors that affect the survival time of patients with kidney failure and determine the MARS model. The MARS approach is obtained from a combination of functional basis, maximum interaction, and minimum observation by trial and error. Based on the model that has been formed using the MARS approach, it is found that the most influential variables on the survival time of patients with kidney failure are age, urea levels, and creatine levels.
 Key words: Renal failure, hemodialysis, survival analysis, nonparametric, MARS

Effects of Rumen-Protected Creatine Pyruvate on Meat Quality, Hepatic Gluconeogenesis, and Muscle Energy Metabolism of Long-Distance Transported Beef Cattle

Pre-slaughter long-distance transport resulted in a rapid depletion of muscle glycogen and led to a higher rate of dark, firm and dry (DFD) meat. Therefore, enhancing muscle glycogen reserves is critical for beef cattle prior to transportation. Creatine pyruvate (CrPyr) can provide simultaneous pyruvate and creatine and both are proven to promote the glycogen reserves. This study aimed to investigate the effects of transport treatment and dietary supplementation of rumen-protected (RP)-CrPyr on the meat quality, muscle energy metabolism, and hepatic gluconeogenesis of beef cattle. Twenty 18 month-old male Simmental crossbred cattle (659 ± 16 kg) were allotted 4 treatments based on a 2 × 2 factorial arrangement with two RP-CrPyr levels (140 g/d or 0 g/d) and two transport treatments (12 h or 5 min): ST_CrPyr0, ST_CrPyr140, LT_CrPyr0 and LT_CrPyr140. Three cattle per group were slaughtered after 30 days of feeding. The interaction of transport and RP-CrPyr had a significant effect on the muscle pH45 min, redness, glycogen content, GP, and AMP level (P < 0.05). Compared with short-distance transport, long-distance transport increased the muscle pH45 min value, redness, yellowness, drip loss, creatine level (P < 0.05), decreased muscle glycogen content, glycolytic potential (GP), and liver glucose amount (P < 0.05). Supplementation of RP-CrPyr decreased the activities of creatine kinase and lactate dehydrogenase in serum, muscle pH24 h value, redness, yellowness, lactate content, AMP level, and AMP/ATP (P < 0.05), increased the muscle glycogen content, GP, hexokinase activity, ATP and ADP levels, and ATP/ADP, liver pyruvate and glucose contents, activity of pyruvate carboxylase in the liver of cattle than those in the nonsupplemented treatments (P < 0.05). These results indicated that dietary RP-CrPyr supplementation might be favorable to improve meat quality and regulatory capacity of energy metabolism of beef cattle suffering long-distance transport followed with recovery treatment by increasing muscle glycogen storage, energy supply, and hepatic gluconeogenesis.

Cyclocreatine Suppresses Creatine Metabolism and Impairs Prostate Cancer Progression.

Enhanced creatine uptake drives prostate cancer progression and confers a metabolic vulnerability to treatment with the creatine analog cyclocreatine.

PERFIL NUTRICIONAL DE IDOSOS HOSPITALIZADOS

This study aimed to know the nutritional profile of elderly patients hospitalized in a public hospital. A retrospective survey of 250 nutritional assessment sheets of elderly people admitted to the hospital service was carried out, where anthropometric data, nutritional diagnosis and laboratory tests were collected. Prevalence of low weight and lean mass depletion was detected among the oldest old, as well as a significant correlation between the levels of albumin and creatine with the muscular depletion measured by the calf circumference (CP). Regarding food intake, it was observed that 14% ingested a lower amount than prescribed, and the long-lived elderly people needed more food intervention. It is concluded that the incidence of nutritional risk and malnutrition among hospitalized elderly people is higher among long-lived elderly people, and that in this group there is a negative correlation between serum albumin levels with body mass index and CP.

Systematic Investigations on the Metabolic and Transcriptomic Regulation of Lactate in the Human Colon Epithelial Cells.

Lactate, primarily produced by the gut microbiota, performs as a necessary “information transmission carrier” between the gut and the microbiota. To investigate the role of lactate in the gut epithelium cell–microbiota interactions as a metabolic signal, we performed a combinatory, global, and unbiased analysis of metabolomic and transcriptional profiling in human colon epithelial cells (Caco-2), using a lactate treatment at the physiological concentration (8 mM). The data demonstrated that most of the genes in oxidative phosphorylation were significantly downregulated in the Caco-2 cells due to lactate treatment. Consistently, the levels of fumarate, adenosine triphosphate (ATP), and creatine significantly decreased, and these are the metabolic markers of OXPHOS inhibition by mitochondria dysfunction. The one-carbon metabolism was affected and the polyol pathway was activated at the levels of gene expression and metabolic alternation. In addition, lactate significantly upregulated the expressions of genes related to self-protection against apoptosis. In conclusion, lactate participates in gut–gut microbiota communications by remodeling the metabolomic and transcriptional signatures, especially for the regulation of mitochondrial function. This work contributes comprehensive information to disclose the molecular mechanisms of lactate-mediated functions in human colon epithelial cells that can help us understand how the microbiota communicates with the intestines through the signaling molecule, lactate.

Duodenal Necrosis and Nonvariceal Digestive Bleeding After Terlipressin Administration for Treatment of Hepatorenal Syndrome: a Case Report of a Novel Side Effect of a Commonly Used Drug

BackgroundTerlipressin is widely used for treatment of hepatorenal syndrome and variceal bleeding in cirrhotic patients. However, it may be associated with side effects, especially those related to vasoconstriction, such as myocardial infarction or intestinal ischemia. This is a case report of a cirrhotic patient with nonvariceal upper gastrointestinal bleeding after duodenal necrosis due to the use of terlipressin, a novel side effect not yet described in literature to the best of our knowledge. Case reportA 51-year-old male patient, with alcoholic liver cirrhosis and hepatitis C virus infection, was admitted presenting oliguria associated with severe ascites and lower limb edema. His Model for End Stage Liver Disease–Sodium score was 19 and his serum creatine level was 2.12 mg/dL. Albumin infusion was performed for 48 hours, but his serum creatinine level reached 3.46 mg/dL. Terlipressin infusion was started in continuous infusion and serum creatinine levels progressively decreased. However, the patient presented hemorrhagic shock secondary to hematemesis after 7 days. Upper digestive endoscopy showed an extensive ulcerated lesion in the duodenal bulb, reaching 70% of its lumen, with hematic residues and necrotic foci. Terlipressin was suspended and proton pump inhibitors were started. Despite intensive care, the patient developed severe encephalopathy and reentrant seizures. He eventually died 10 days after the bleeding event. ConclusionsWe described a case of nonvariceal upper gastrointestinal bleeding secondary to duodenal necrosis, which was caused by visceral ischemia induced by terlipressin. Given its fatality potential, this novel side effect should be remembered when using this medication in cirrhotic patients.

Lower Posterior Cingulate N-Acetylaspartate to Creatine Level in Early Detection of Biologically Defined Alzheimer's Disease.

Alzheimer’s disease (AD) was recently defined as a biological construct to reflect neuropathologic status, and both abnormal amyloid and tau are required for a diagnosis of AD. We aimed to determine the proton MR spectroscopic (1H-MRS) patterns of the posterior cingulate in biologically defined AD. A total of 68 participants were included in this study, comprising 37 controls, 16 early AD, and 15 late AD, who were classified according to their amyloid and tau status and presence of hippocampal atrophy. Compared with controls, early AD showed lower N-acetylaspartate (NAA)/creatine (Cr) (p = 0.003), whereas late AD showed lower NAA/Cr and higher myoInositol (mI)/Cr (all with p < 0.05). Lower NAA/Cr correlated with a greater global amyloid load (r = −0.47, p < 0.001) and tau load (r = −0.51, p < 0.001) and allowed a discrimination of early AD from controls (p < 0.001). Subgroup analysis showed that NAA/Cr also allowed a differentiation of early AD from controls in the cognitively unimpaired subjects, with an area under the receiver operating characteristics curve, sensitivity, and specificity of 0.96, 100%, and 83.8%, respectively. Lower posterior cingulate NAA levels may help to inform underlying neuropathologic changes in the early stage of AD.

The Effect of Cold Plasma on pH, Creatine, and the Concentration of the Most Trace Elements in Human's Nails by Using X-ray Fluorescent Method

The aim of this study is to determine the effect of cold plasma on nails pH, creatine levels and the accumulative of some trace elements in humans nails. Creatine levels in the blood, as well as pH and trace elements, were measured before and after (1, 2) months of plasma exposure in both gender (men and women) between the ages of 22 and 25 years. Nails are exposed to cold plasma with a voltage of (175 volts) and (2 gas flow). After one month of exposure, there was no significant change in the levels of all parameters, but after 2 months, the concentration of creatine and pH had reached a near- neutral value. In both men and women, calcium concentration increased and showed a positive response to cold plasma, while the vanadium element concentration did not change over time and remained stable at (7.3×10-4). The results clearly suggest that men respond more than women. The best results were obtained after two-month period of exposure.

Multimorbidity in elderly patients with acute coronary syndrome: insights from BleeMACS registry

Objective: To assess the prevalence, pattern and outcome of multimorbidity in elderly patients with acute coronary syndrome (ACS). Methods: Secondary analysis was performed based on the data from the BleeMACS registry, which was conducted between 2003 and 2014. We stratified elderly patients (≥65 years) according to their multimorbidity. Multimorbidity was defined as two or more chronic diseases in the same individual. Kaplan-Meier methods were used to estimate 1 year event rates for each endpoint, and comparisons between the study groups were performed using the log-rank test. The primary endpoint was net adverse clinical events (NACE), which is a composite of all-cause mortality, myocardial infarction, or bleeding. Results: Of 7 120 evaluable patients, 6 391 (89.8%) were with morbidity (1 594 with 1, 2 156 with 2, and 2 641 with ≥3 morbidity). Patients with morbidity were older, percent of female sex and non-ST-elevation acute coronary syndromes and implantation rate with drug-eluting stents and blood creatine level were higher compared to patients without morbidity. Compared with the patients without morbidity, the proportion of participants with oral anticoagulant increased in proportion to increased number of morbidities (5.8% vs. 6.4% with 1 morbidity, 7.3% with 2 morbidities, 9.0% with ≥3 morbidities, P trend<0.01) and the proportion of participants with clopidogrel prescription decreased in proportion to increased number of morbidity (91.9% vs. 89.7% with 1 morbidity, 87.9% with 2 morbidities, 88.6% with ≥3 morbidities, P trend = 0.01). During 1 year follow-up, compared with those with no morbidity, the hazard ratio (HR) and 95% confidence interval (CI) of risk of NACE for those with 1, 2, and ≥ 3 morbidities was 1.18 (0.86-1.64), 1.49 (1.10-2.02), and 2.74 (2.06-3.66), respectively (P < 0.01). Multimorbidity was not associated with an increased risk of bleeding of various organs (P>0.05). Conclusion: Multimorbidity is common in elderly patients with ACS. These patients might benefit from coordinated and integrated multimorbidity management by multidisciplinary teams.

AB0064 PHARMACOLOGICAL INHIBITION OF IL-6/JAK/STAT AXIS INCREASES MUSCLE MASS IN AN EXPERIMENTAL MODEL OF SARCOPENIA ASSOCIATED TO RHEUMATOID ARTHRITIS

BackgroundSarcopenia is a frequent comorbidity of rheumatoid arthritis (RA) due to an imbalance in muscle remodelling with dominance of catabolism over anabolism. IL-6/JAK/STAT axis is of particular importance in this regulation because of its dual activity. According to local and acute factors, it promotes muscle healing and hypertrophy, whereas in chronic inflammation, this signalling substantially increases muscle catabolism activating pro-atrophic pathways involving atrogene expression and ubiquitin proteasome system (UPS). JAK/STAT blockade suppresses muscle wasting induced by IL-6, through STAT3 activation. Interestingly, different clinical trials have shown that JAK inhibitors produce an asymptomatic increase in serum creatine kinase (CK) and creatinine levels in RA patients, suggesting an impact on muscle.ObjectivesTo evaluate the effect of JAK inhibition and its effect in muscle remodelling in an experimental model that accurately mimics human rheumatoid sarcopenia.MethodsAn experimental model of antigen-induced arthritis (AIA) was carried out in 14 rabbits by immunization against ovalbumin followed by 4 intra-articular (i.a) injections of this protein. One week after the first i.a injection, 7 of these rabbits received tofacitinib (TOFA, orally 10mg/kg/day) for 2 wk. Animals were euthanized one day after the last i.a injection, when tibialis anterior (TA), extensor digitorum longus (EDL) and gastrocnemius (GN) were isolated from both hind limbs. Histological changes and ATPase staining were analysed in TA, while the number of myonuclei was evaluated in EDL fibres by immunofluorescence studies. C-reactive protein (CRP) and myostatin (MSTN) serum concentration were determined by ELISA. The gene expression of proinflammatory cytokines (IL-1β, IL-6, TNF-α, MCP-1), atrogenes (Atrogin-1, MuRF-1) and MSTN was measured by quantitative PCR, while proliferative muscle marker (PAX-7), differentiation muscle markers (MyoD, Myogenin), pSTAT3, pSTAT1, MSTN and CK protein expression was analysed by western blot in GN. Creatine presence in GN was analysed by a colorimetric assay.ResultsA significant increase in body weight was observed in the AIA+TOFA group vs. AIA at the end of the study. A significant increase in TA cross-sectional area and diameter in the AIA+TOFA, in comparison to AIA, was found, while the decrease in the area of type II fibres observed in the AIA animals was not noticed in AIA+TOFA. Moreover, the number of myonuclei in the EDL that was increased in the AIA group when compared to healthy animals, was significantly decreased in AIA+TOFA. However, systemic inflammation measured by CRP was not modified by TOFA treatment at the end of the study, in comparison to AIA, and so did serum MSTN concentration. TOFA evoked a significant reduction in the gene expression of IL-6, MCP-1, atrogin-1 and MuRF-1 in GN in comparison to untreated AIA rabbits. Notably, AIA+TOFA showed higher protein levels of CK and lower creatine compared to AIA in muscle. Simultaneously, no differences in the proliferative marker PAX-7 were found between groups, while AIA rabbits showed an increase in the differentiation markers MyoD and Myogenin in the muscle that was prevented in AIA+TOFA.ConclusionThese data provide novel insights into the effects of JAK inhibitors in muscle remodelling during rheumatoid cachexia. Despite an elevated systemic inflammatory status, JAK inhibition was able to rapidly increase muscle mass through attenuating IL-6/JAK/STAT activation, decreasing atrogene expression, and restoring to baseline the muscle cell differentiation markers in the tissue. The increase in muscle mass was accompanied by an increase in CK presence, supporting the role of CK as a valuable marker of muscle gain following treatment with JAK inhibitors. However, the low levels of MCP-1 and the disorganization of muscle fibre myonuclei raise the question of whether these treatments could trigger a complete regeneration of muscle fibre cell or just hypertrophy of cells already present.Disclosure of InterestsIsmael Bermejo: None declared, Sandra Pérez-Baos: None declared, Juan Pablo Medina: None declared, Paula Gratal: None declared, Ivan Prieto-Potín: None declared, Raquel Largo: None declared, Gabriel Herrero-Beaumont Grant/research support from: The Bone and Joint Research Unit has received funding from several pharmaceutical laboratories (Pfizer, LILLY...).

Physiologically-Based Pharmacokinetics Modeling for Hydroxychloroquine as a Treatment for Malaria and Optimized Dosing Regimens for Different Populations.

Malaria is a severe parasite infectious disease with high fatality. As one of the approved treatments of this disease, hydroxychloroquine (HCQ) lacks clinical administration guidelines for patients with special health conditions and co-morbidities. This may result in improper dosing for different populations and lead them to suffer from severe side effects. One of the most important toxicities of HCQ overdose is cardiotoxicity. In this study, we built and validated a physiologically based pharmacokinetic modeling (PBPK) model for HCQ. With the full-PBPK model, we predicted the pharmacokinetic (PK) profile for malaria patients without other co-morbidities under the HCQ dosing regimen suggested by Food and Drug Administration (FDA) guidance. The PK profiles for different special populations were also predicted and compared to the normal population. Moreover, we proposed a series of adjusted dosing regimens for different populations with special health conditions and predicted the concentration-time (C-T) curve of the drug plasma concentration in these populations which include the pregnant population, elderly population, RA patients, and renal impairment populations. The recommended special population-dependent dosage regimens can maintain the similar drug levels observed in the virtual healthy population under the original dosing regimen provided by FDA. Last, we developed mathematic formulas for predicting dosage based on a patient’s body measurements and two indexes of renal function (glomerular filtration rate and serum creatine level) for the pediatric and morbidly obese populations. Those formulas can facilitate personalized treatment of this disease. We hope to provide some advice to clinical practice when taking HCQ as a treatment for malaria patients with special health conditions or co-morbidities so that they will not suffer from severe side effects due to higher drug plasma concentration, especially cardiotoxicity.

Morphological Studies of the Left Ventricle in the Creatine Deficiency Mice Model

IntroductionHeart failure is the major cause of death characterized by changes in myocardial energetics, including a reduced level of creatine. In organs with high energy demand such as the heart, creatine is taken up by cardiomyocytes via creatine transporter with subsequent transformation into phosphocreatine, which controls by creatine kinase. This system functions as shuttles high‐energy phosphates from mitochondria to contractile elements such as the myofibril, which utilize 70 % of total produced energy by mitochondria. For the past decades, many studies tried to understand whether a reduced level of creatine affects the myocardial function leading to the failing heart. However, most of the results from these studies have been contradictory. The present study describes the detailed morphologic changes of cardiomyocytes of the left ventricle (LV) of mice with whole‐body creatine deficiency due to knockout of the biosynthetic enzyme (guanidinoacetate N‐methyltransferase, GAMT).Methods &amp; ResultsThe present study used GAMT‐/‐ mice model with the unique metabolic fingerprint of zero creatine similar to those in human GAMT deficiency. The histological and transmission electron microscopy (TEM) studies of LV myocardium in GAMT‐/‐ mice showed cardiac hypertrophy and increased collagen accumulation in the myocardial interstitium compared to the wild‐type (WT) mice. The TEM examination showed irreversible destructive ultrastructure changes of cardiomyocytes in conjunction with insufficient adaptive protein synthesis accompanied by focal and diffuse lysis of myofilaments in cardiac myocytes. The mitochondrial changes were characterized by cristae homogenization and fragmentation in association with cluster formation. The volume of density of mitochondria (VvMt), myofibrils (VvMf), and their ratios (VvMt/VvMf), along with the coefficient of energy efficiency of mitochondria (CEEM) have been examined in GAMT‐/‐ mice in comparison to WT. We established that VvMt, VvMf, VvMt/VvMf, and CEEM were all significantly reduced. Further, destructive changes in the nucleus and nuclei, focal degradation of sarcoplasm, increases autophagy, are all evidence of inadequate adaptive protein synthesis in cardiac myocytes.ConclusionsThese studies of GAMT‐/‐ mice demonstrated that creatine deficiency promotes decreased VvMt/VvMf and CEEM in LV myocytes, which may contribute to the development progression of heart failure and in conjunction with insufficient adaptive protein synthesis contribute to irreversible ultrastructure restructuring of cardiomyocytes with loss contractile myocardial function.

Effects of pharmacological treatment on metabolomic alterations in animal models of depression

Numerous studies have investigated metabolite alterations resulting from pharmacological treatment in depression models although few quantitative studies explored metabolites exhibiting constant alterations. This study aimed to identify consistently dysregulated metabolites across such studies using a knowledgebase-driven approach. This study was based on 157 studies that identified an assembly of 2757 differential metabolites in the brain, blood, urine, liver, and feces samples of depression models with pharmacological medication. The use of a vote-counting approach to identify consistently upregulated and downregulated metabolites showed that serotonin, dopamine, norepinephrine, gamma-aminobutyric acid, anandamide, tryptophan, hypoxanthine, and 3-methoxytyramine were upregulated in the brain, while quinolinic acid, glutamic acid, 5-hydroxyindoleacetic acid, myo-inositol, lactic acid, and the kynurenine/tryptophan ratio were downregulated. Circulating levels of trimethylamine N-oxide, isoleucine, leucine, tryptophan, creatine, serotonin, valine, betaine, and low-density lipoprotein were elevated. In contrast, levels of alpha-d-glucose, lactic acid, N-acetyl glycoprotein, glutamine, beta-d-glucose, corticosterone, alanine, phenylacetylglycine, glycine, high-density lipoprotein, arachidonic acid, myo-inositol, allantoin, and taurine were decreased. Moreover, 12 metabolites in urine and nine metabolites in the liver were dysregulated after treatment. Pharmacological treatment also increased fecal levels of butyric acid, acetic acid, propionic acid, and isovaleric acid. Collectively, metabolite disturbances induced by depression were reversed by pharmacological treatment. Pharmacological medication reversed the reduction of brain neurotransmitters caused by depression, modulated disturbance of the tryptophan-kynurenine pathway and inflammatory activation, and alleviated abnormalities of amino acid metabolism, energy metabolism, lipid metabolism, and gut microbiota-derived metabolites.

Cardio-protective effects of terminalia catappa leaves and terminalia chebula fruit extract in doxorubicin-induced cardiomyopathy in rats

Background The cardio-protective effects of Terminalia catappa and Terminalia chebula are well-recognized in Ayurveda for its antimicrobial, antidiabetic and antioxidant potentials. The present study evaluates the effects of T. catappa leaves (Tct.LE) and T. chebula fruits (Tce.FE) against doxorubicin (DOX)-induced rats through analysis of the cardiac biomarkers, tricarboxylic acid (TCA) cycle enzymes and respiratory chain enzymes for their cardio-protective properties. Materials and methods This study includes 42 adult male Albino Wistar rats randomized into seven groups for 21-days. Groups were categorized as control; DOX (1.5 mg/kg) induced negative control; basal diet with 300 mg/kg of Tct.LE, with 300 mg/kg Tce.FE; DOX with 300 mg/kg of Tct.LE, Tce.FE, and propranolol (25 mg/kg). Results and discussion The doses of 300 mg/kg of both plants have a significant effect on the TCA cycle, respiratory and lysosomal enzymes activity. The troponin levels are significantly reduced in plant treated group than the DOX-treated rats when compared with the control and propranolol treated group. Likewise, the increased level of creatine kinase-muscle/MB, creatine kinase and lipid profile in the DOX-treated animals were significantly reduced upon being treated with extracts. Conclusion The cardio-protective activity of Tct.LE leaves and Tce.FE indicate its potential use in the management of cardiovascular diseases.

Man With Epigastric Pain

An 84-year-old man presented to the emergency department with a 1-day history of dull epigastric pain, decreased appetite, and frequent hiccups. He had a remote perforated gastric ulcer and had, therefore, undergone subtotal gastrectomy with Billroth II anastomosis. His blood pressure was 150/91 mm Hg and pulse rate was 86 beats/min. A physical examination was noteworthy only for mild epigastric tenderness. His WBC count was 6,760/μL, creatine level was 1.4 mg/dL, lipase level was 1,866 U/L, and total bilirubin level was 0.68 mg/dL.

Acute and Subacute Toxicity Studies of Cyperus Papyrus Ash on Wistar Albino Rats

Background: Acute and subacute toxicity screenings of medicinal plants are the fastest way to evaluate the toxicological profiles of medicinal plants. It helps to have a quick idea of the harm or safety potency of drugs. This study aims to conduct an acute and subacute oral toxicity study on the Cyperus Papyrus (CP) ash in Wistar albino rats. CP is traditionally used for managing painful spasms, eye diseases, ulcers, fever, diarrhea, and inflammations. Further study is required to reflect the safety profile of this plant ash. Methods: Acute oral toxicity study of the CP ash was evaluated by using a dose of 2000 mg/kg body weight on rats according to the Organization for Economic Co-operation and Development (OECD) guidelines using the Aot425 software. Subacute oral toxicity was carried out on 4 groups of 6 rats, at doses of 175 mg/kg, 550 mg/kg, 1750 mg/kg, and 1750 mg/kg. The recovery group (control group) received water according to OECD 407 guidelines for consecutive 28 days. At the end of the experiments (day 29), all rats were weighed and sacrificed except the rats of the recovery group which were continued without ash administration for extra 14 days and then weighed and sacrificed. Subsequently, the hematological parameters, plasma biochemical parameters, and histopathological examination were carried out. Results: Upon completion of the acute toxicity, no deaths or signs of acute oral toxicity were observed. Hematologic observations after oral subacute toxicity included a decrease in hematocrit percentage, mean corpuscular volume, and lymphocyte percentage, while there was a slight increase in the mean corpuscular hemoglobin concentration, however, it returned to the normal range in the recovery group. Biochemical tests showed a mild increase in the serum creatine and aspartate aminotransferase levels but they also returned to their normal range in the recovery group. No morphological changes in the kidney, liver, lung, spleen, heart or small intestine were observed after the histopathological examinations. Conclusion: Dried ash of CP is considered to be safe and non-toxic at acute exposure and as the lethal dose 50% value exceeds 2000 mg/kg body weight, it has a mild reversible effect on some hematological and biochemical parameters while no morphological changes of vital organ histopathology occur.

Therapeutic effect of finasteride through its antiandrogenic and antioxidant role in a propionic acid-induced autism model: Demonstrated by behavioral tests, histological findings and MR spectroscopy

BackgroundAutism is a clinically defined neurodevelopmental disorder with unknown origin characterized by significant social, communication and behavioral challenges. Although it can be a lifelong condition, treatments can help alleviate symptoms and enhance a patient's quality of life. PurposeWe aimed to assess the therapeutic potential of finasteride in autism with biochemical markers, histopathological evaluation, behavioral tests and radiological imaging. Materials and methodsPropionic acid (PPA) was injected intraperitoneally into 20 out of 30 rats for 5 days to establish an autism model. Rats were randomly assigned into four groups: control group (no procedure was applied, n = 10), placebo group (intraperitoneal PPA + 1 ml/kg/day % 0.9 NaCl saline was given via oral gavage for 15 days, n = 10) and treated group (intraperitoneal PPA + 5 mg/kg/day of finasteride was given via oral gavage for 15 days, n = 10). After 4 days of behavioral tests, magnetic resonance spectroscopy (MRS) was performed for measuring creatine and lactate levels. All animals were sacrificed for histopathological examination and biochemical analysis of brain tissue. ResultsMDA, NFκB, TNF-α, IL-2, IL-17A and lactate levels in brain homogenates were significantly increased in the placebo group compared to the control group, while Nfr2 levels were decreased; and the levels of all biochemical markers were reversed by finasteride treatment. A significant improvement was observed in autism-like behaviors in rats treated with finasteride compared to the placebo group. Further, the creatine and lactate levels in corpus striatum in MRS, the neuronal counts and glial activity of the hippocampus and cerebellum were closer to the control group in the finasteride-treated group compared to the placebo group. ConclusionFinasteride led significant improvement in autism-like symptoms with its antioxidant effect through Nrf2 modulation in addition to its anti androgen effect.

A Japanese Dose of Prasugrel versus a Standard Dose of Clopidogrel in Patients with Acute Myocardial Infarction from the K-ACTIVE Registry.

Background: Dual antiplatelet therapy (DAPT) with aspirin plus P2Y12 inhibitor is used as a standard therapy for patients with acute myocardial infarction (AMI) treated with drug-eluting stents (DESs). In Japan, clopidogrel was the major P2Y12 inhibitor used for a decade until the new P2Y12 inhibitor, prasugrel, was introduced. Based on clinical studies considering Japanese features, the set dose for prasugrel was reduced to 20 mg as a loading dose (LD) and 3.75 mg as a maintenance dose (MD); these values are 60 and 10 mg, respectively, globally. Despite this dose discrepancy, little real-world clinical data regarding its efficacy and safety exist. Methods: From the K-ACTIVE registry, based on the DAPT regimen, patients were divided into a prasugrel group and a clopidogrel group. The ischemic event was a composite of cardiovascular death, non-fatal MI, and non-fatal stroke. The bleeding event was type 3 or 5 bleeding based on the Bleeding Academic Research Consortium (BARC) criteria. Results: Substantially more patients were prescribed prasugrel (n = 2786) than clopidogrel (n = 890). Clopidogrel tended to be selected over prasugrel in older patients with numerous comorbidities. Before adjustments were made, the cumulative incidence of ischemic events at 1 year was significantly greater in the clopidogrel group than in the prasugrel group (p = 0.007), while the cumulative incidence of bleeding events at 1 year was comparable between the groups (p = 0.131). After adjustments were made for the age, sex, body weight, creatine level, type of AMI, history of MI, approach site, oral anticoagulation therapy, presence of multivessel disease, Killip classification, and presence of intra-aortic balloon pumping, both ischemic and bleeding events became comparable between the groups. Conclusion: A Japanese dose of prasugrel was commonly used in AMI patients in the real-world database. Both the prasugrel and clopidogrel groups showed comparable rates of 1 year ischemic and bleeding events.

Effect of crude Ganoderma applanatum polysaccharides as a renoprotective agent against carbon tetrachloride-induced early kidney fibrosis in mice.

Background and Aim:Interstitial fibrosis is the final stage of chronic kidney injury, which begins with an inflammatory process. Crude Ganoderma applanatum polysaccharides are known to have anti-inflammatory properties. The potential role of crude G. applanatum polysaccharides in renal fibrosis through pro-inflammatory cytokines needs further investigation. This study aimed to determine the renoprotective effect of crude G. applanatum polysaccharide extract in mice with carbon tetrachloride (CCL4)-induced early kidney fibrosis.Materials and Methods:This study was conducted for 4 weeks using 24 male BALB/c mice selected for their metabolic stability. The mice were randomly divided into six groups, including control (CG), model (MG), silymarin group and crude G. applanatum polysaccharide extract groups comprising doses of 25, 50, and 100 mg/kg body weight. After sacrificing the mice, whole blood was analyzed for urea and creatine levels, and kidney tissue was prepared to assess tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), hyaluronic acid (HA), and laminin levels, both using enzyme-linked immunosorbent assay. Kidney histology was determined using hematoxylin and eosin staining, while the extracellular matrix (ECM) components were stained using Masson’s trichome staining. The α-smooth muscle actin (α-SMA) concentration was determined using immunohistochemistry. These parameters were measured to determine the effectiveness of the crude G. applanatum polysaccharide extract in preventing interstitial fibrosis.Results:Administration of crude G. applanatum polysaccharides effectively prevented increases in kidney weight and physiological enzymes, pro-inflammatory cytokines, and ECM production compared with those in the MG, as evidenced by the low levels of urea, creatinine, TNF-α, IL-6, HA, and laminin. Histopathological results also showed that crude G. applanatum polysaccharides prevented the occurrence of inflammatory infiltration, desquamated nuclei, cytoplasm debris, rupture at the brush border, dilatation of the glomeruli space and lumen of the proximal tubule, and necrotic cells compared with the MG. Masson’s trichrome staining revealed lower collagen levels in the interstitial tubules of kidney tissue than those in the MG. Immunohistochemical analysis revealed low α-SMA expression in the crude G. applanatum polysaccharides treatment groups than that in the MG.Conclusion:The crude polysaccharide extract of G. applanatum has a protective effect that prevents the progression of kidney fibrosis in mice.