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To date, good experimental animal models of renal anemia are not available. Therefore, the purpose of this study was to establish a novel approach to induce chronic kidney disease (CKD) with severe anemia by oral administration of adenine in rodents. Adenine was administered to 6-week-old male C57BL/6 mice (25 and 50 mg/kg body weight) by oral gavage daily for 28 days. Serum creatinine and BUN as well as hematocrit, hemoglobin (Hb) and plasma erythropoietin (EPO) levels were monitored to assess renal function and anemia, respectively. Adenine at 25 mg/kg for 28 days slightly increased plasma creatinine levels, but did not induce anemia. In contrast, 50 mg/kg of adenine daily for 28 days showed severe renal dysfunction (plasma creatinine 1.9 ± 0.10 mg/dL) and anemia (hematocrit 36.5 ± 1.0% and EPO 28 ± 2.4 pg/mL) as compared with vehicle-treated mice (0.4 ± 0.02 mg/dL, 49.6 ± 1.6% and 61 ± 4.0 pg/mL, respectively). At the end of experiment, level of Hb also significantly reduced in 50 mg/kg adenine administration group. Remarkable histological changes of kidney tissues characterized by interstitial fibrosis and cystic appearance in tubules were observed in 50 mg/kg of adenine treatment group. These results have demonstrated that oral dosing with adenine at 50 mg/kg for 28 days is suitable to induce a stable anemia associated with CKD in mice.

Scientific studyAcid Rain attacked South West Sweden 1960–1990, making well water acid, causing Cu dissolution from pipes, disturbing intestines. In a scientific study Ca was 6 times higher in alkaline well waters and hair. Women drinking acid water were unhealthy.Case studiesCase studies: 1 (woman): Scleroderma had caused shortened finger tips, and loss of hair. Urinary pH was 5. Hair analysis showed severe mineral imbalances. After 1.5 years of treatment with supplements and increasing urinary pH with NaHCO3, symptoms disappeared. 2 (woman): Fibromyalgia, cataract, constipation and basal carcinoma was treated by increasing urinary pH with limestone, and supplements. 3 (man). Fe in drinking water, 3.4 mg/L, had caused intestinal disturbances and subsequent symptoms. Fe was elevated in hair. Aloe vera juice, lactic bacteria and digestive enzymes healed his intestines. Mg, antagonist to Fe, decreased severity of Fe overload. Drinking water guideline of 0.2 mg Fe/L is suggested.

The substitution of fish resources as ingredients for aquafeeds by those based on vegetable sources is needed to ensure aquaculture sustainability in the future. It is known that Senegalese sole (Solea senegalensis) accepts high dietary content of plant ingredients without altering growth or flesh quality parameters. However, scarce information is available regarding the long-term impact of vegetable diets (combining the inclusion of both vegetable protein and oils) on the stress response and immunity of this fish species. This study aims to evaluate the concomitant effect of the extended use of vegetable protein-based diets with fish oil (FO) replacement (0, 50 or 100%) by vegetable oils (VO), on the response to acute (10 min) or prolonged (4 days) stress, induced by thermal shock. Plasma levels of cortisol, glucose and lactate as well as hepatic levels of glucose, glycogen and lactate were evaluated as primary and secondary responses to stress, 6 and 18 months after feeding the experimental diets (6 and 18 MAF). The brain monoaminergic activity in telencephalon and hypothalamus, and non-specific immune parameters were also evaluated. As expected, thermal shock induced an increase in values of plasma parameters related to stress, which was more evident in acute than in prolonged stress. Stress also affected lactate levels in the liver and the values of the alternative complement pathway-ACH50 in the plasma. Dietary substitution of FO induced an effect per se on some parameters such as decreased hepatic glucose and glycogen levels and peroxidase activity in plasma as well enhanced serotonergic activity in brain of non-stressed fish. The results obtained in some parameters indicate that there is an interaction between the use of vegetable diets with the physiological response to thermal stress, as is the case of the hepatic lactate, serotonergic neurotransmission in brain, and the activity of ACH50 in plasma. These results suggest that the inclusion of VO in plant protein based diets point to a slightly inhibited stress response, more evident for an acute than a prolonged stress. © 2018 Conde-Sieira et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Cadmium (Cd) and lead (Pb) pose a serious threat to human health because of its carcinogenicity. China ranks first according to the Global Cancer Report for 2014 in newly diagnosed gastrointestinal cancers and cancer deaths. The aim of the present study was to evaluate the association of Cd and Pb burden with the risk of gastrointestinal cancers in a hospital-based case-control study from southern regions of China, Chaoshan area. A total of 279 hospitalized patients were recruited in this study, of which 167 were gastrointestinal cancer cases (70 esophageal cancer, 51 gastric cancer, and 46 colorectal cancer), and 112 controls were recruited from two hospitals in the Chaoshan area of southeast China. Basic clinical data and information on gender, age, and other demographic characteristics were collected from medical records. Blood Cd and Pb levels were detected by graphite furnace atomizer absorption spectrophotometry (GFAAS). Blood Cd/Pb levels and over-limit ratios between cases and controls were compared by Mann-Whitney U and Kruskal-Wallis H tests. We used logistic regression to estimate odds ratios (ORs) as measures of relative risk and explored the relationships between blood Cd/Pb levels and gastrointestinal cancer risk and clinicopathological characteristics. Median levels of blood Cd and Pb in cases (2.12 and 60.03 μg/L, respectively) were significantly higher than those of controls (1.47 and 53.84 μg/L, respectively). The over-limit ratios for Cd (≥ 5 μg/L) and Pb (≥ 100 μg/L) in the cases were both higher than that of controls. Blood Cd levels had a tendency to accumulate in the human body with gender, age, and tobacco smoking, while blood Pb levels only were associated with tobacco smoking. The logistic regression model illustrated that gastrointestinal cancers were significantly associated with blood Cd levels and blood Pb levels. The concentrations of Cd and Pb in patients with T3 + T4 stage were markedly higher than in patients with T1 + T2. On the other hand, blood Cd levels were dramatically increased in the distant –metastasis (M1). Blood Cd and Pb levels are significantly higher in gastrointestinal cancers compared to controls. Cd and Pb appear to be risk factors for gastrointestinal cancers in Chaoshan region, and higher levels of Cd and Pb may promote the occurrence and progression of gastrointestinal cancers.

This study investigates the impact of Body Mass Index (BMI) and Waist-to-Hip Ratio (WHR) on Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) levels, as well as the mediating role of lipid parameters: total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. Understanding these associations is crucial for exploring the interplay between obesity, fatty liver disease, liver function impairment, and dyslipidemia. Conducted in Nantong City, Jiangsu Province, from July to September 2024, this research used a convenience sampling method involving 1,816 participants. Generalized Linear Models (GLM) and Restricted Cubic Splines (RCS) analyzed BMI/WHR’s relationship with ALT/AST, while causal mediation analysis assessed lipid parameters’ mediating effects. The findings indicated a positive correlation between both BMI and WHR with AST and ALT levels. The lipid indicators significantly mediated the relationship between BMI/WHR and AST/ALT, suggesting that obesity correlates with elevated liver enzyme levels and that blood lipid abnormalities may play an important intermediary role. This study enhances the understanding of interactions among obesity, fatty liver disease, liver function impairment, and dyslipidemia. It underscores the importance of addressing lipid abnormalities in managing obesity-related liver disease and calls for future research to explore underlying mechanisms and develop targeted interventions.

RationaleWhile one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges.ObjectivesHere, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders.MethodsThe relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated.ResultsFifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120–270 ng/ml and 180–380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders.ConclusionsHigh interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers.

Functional magnetic resonance imaging (fMRI) is currently one of the most popular technologies for measuring brain activity in both research and clinical contexts. However, clinical constraints often result in short fMRI scan durations, limiting the diagnostic performance for brain disorders. To address this limitation, we developed an end‐to‐end frequency‐specific dual‐attention‐based adversarial network (FDAA‐Net) to extend the time series of existing blood oxygen level‐dependent (BOLD) data, enhancing their diagnostic utility. Our approach leverages the frequency‐dependent nature of fMRI signals using variational mode decomposition (VMD), which adaptively tracks brain activity across different frequency bands. We integrated the generative adversarial network (GAN) with a spatial–temporal attention mechanism to fully capture relationships among spatially distributed brain regions and temporally continuous time windows. We also introduced a novel loss function to estimate the upward and downward trends of each frequency component. We validated FDAA‐Net on the Human Connectome Project (HCP) database by comparing the original and predicted time series of brain regions in the default mode network (DMN), a key network activated during rest. FDAA‐Net effectively overcame linear frequency‐specific challenges and outperformed other popular prediction models. Test–retest reliability experiments demonstrated high consistency between the functional connectivity of predicted outcomes and targets. Furthermore, we examined the clinical applicability of FDAA‐Net using short‐term fMRI data from individuals with autism spectrum disorder (ASD) and major depressive disorder (MDD). The model achieved a maximum predicted sequence length of 40% of the original scan durations. The prolonged time series improved diagnostic performance by 8.0% for ASD and 11.3% for MDD compared with the original sequences. These findings highlight the potential of fMRI time series prediction to enhance diagnostic power of brain disorders in short fMRI scans. BOLD time series were extracted from preprocessed fMRI data and decomposed into intrinsic mode functions (IMFs) using VMD. Prediction was performed on the IMFs using an adversarial approach and a hybrid loss function. The predicted IMFs were inversely transformed and merged to obtain the final signal sequence of the target region.

Background: Atherosclerotic cardiovascular disease (ASCVD) is a preventable type of disease, thus, specifying factors that increase the occurrence of this type of disease is needed. Heavy metals such as cadmium (Cd), lead (Pb), and mercury (Hg) have been suggested as possible factors influencing the development of cardiovascular disease. We aimed to link blood heavy metal levels (Cd, Pb, Hg) with 10-year ASCVD risk scores. Methods: A population of 993 men and 1431 women who participated in the Korea National Health and Nutrition Examination Survey (KNHANES) were included. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) pooled cohort equations risk prediction model and Korean Risk Prediction Model (KRPM) were used as means for risk prediction. Following multivariate adjustment; blood Cd; Pb; and Hg levels were divided into quartiles for analysis using linear trends estimation and multiple regression models. Results: There was an overall positive trend between blood Cd, Pb, and Hg levels and 10-year ASCVD risk scores; KRPM risk score increasing by quartile for blood Cd (men p < 0.0001, women p = 0.0024), Pb (men p = 0.0097, women p = 0.0330), Hg (men p = 0.0096, women p = 0.0030) rates and pooled cohort equations risk score increasing by quartile for Cd (men p < 0.0001, women p = 0.0034) and Hg (men p = 0.0099, women p = 0.0010) with linear trends. Urban population showed a stronger relationship between blood Cd, Pb, and Hg levels and 10-year ASCVD risk score especially among men with multiple regression analysis. Conclusion: Blood Cd, Pb, and Hg levels are associated with ASCVD risk. Thus, they should be considered while developing preventive measures for ASCVD.

The safety and efficacy profile of caspofungin and micafungin in Japanese patients with fungal infections were directly compared in this prospective, randomized, double-blind study. The proportion of patients who developed significant drug-related adverse event(s) (defined as a serious drug-related adverse event or a drug-related adverse event leading to study therapy discontinuation) was compared in 120 patients [caspofungin 50 mg, or 50 mg following a 70-mg loading dose on Day 1 (hereinafter, 70/50 mg) group: 60 patients; micafungin 150 mg: 60 patients]. The overall response rate was primarily evaluated in the per-protocol set (PPS) population. The proportion of patients who developed significant drug-related adverse events was 5.0 % (3/60) in the caspofungin group and 10.0 % (6/60) in the micafungin group [95 % confidence interval (CI) for the difference: −15.9 %, 5.2 %]. The favorable overall response in the PPS population for patients with esophageal candidiasis, invasive candidiasis, and chronic pulmonary aspergillosis including aspergilloma was 100.0 % (6/6), 100.0 % (3/3), and 46.7 % (14/30) in the caspofungin group, and 83.3 % (5/6), 100.0 % (1/1), and 42.4 % (14/33) in the micafungin group, respectively. In Japanese patients with Candida or Aspergillus infections, there was no statistical difference in the safety between caspofungin and micafungin. Consistent with other data on these two agents, the efficacy of caspofungin and micafungin was similar.

Background Friedreich ataxia is a progressive multisystem disorder caused by deficiency of the protein frataxin; a small mitochondrial protein involved in iron sulfur cluster synthesis. Two types of frataxin exist: FXN-M, found in most cells, and FXN-E, found almost exclusively in red blood cells. Treatments in clinical trials include frataxin restoration by gene therapy, protein replacement, and epigenetic therapies, all of which necessitate sensitive assays for assessing frataxin levels. Methods In the present study, we have used a triple quadrupole mass spectrometry-based assay to examine the features of both types of frataxin levels in blood in a large heterogenous cohort of 106 patients with FRDA. Results Frataxin levels (FXN-E and FXN M) were predicted by GAA repeat length in regression models ( R 2 values = 0.51 and 0.27, respectively), and conversely frataxin levels predicted clinical status as determined by modified Friedreich Ataxia Rating scale scores and by disability status ( R 2 values = 0.13–0.16). There was no significant change in frataxin levels in individual subjects over time, and apart from start codon mutations, FXN-E and FXN-M levels were roughly equal. Accounting for hemoglobin levels in a smaller sub-cohort improved prediction of both FXN-E and FXN-M levels from R 2 values of (0.3–0.38 to 0.20–0.51). Conclusion The present data show that assay of FXN-M and FXN-E levels in blood provides an appropriate biofluid for assessing their repletion in particular clinical contexts.