PMID: 

Indian J Radiol Imaging. 2017 Apr-Jun;27(2):141-147. PMID: 28744073

Abstract Title: 

Gadolinium based contrast agents in current practice: Risks of accumulation and toxicity in patients with normal renal function.

Abstract: 

Despite being decked as the most prized compounds in the nugget box of contrast agents for clinical radiologists, and carrying an indisputable tag of safety of the US Food and Drug Administration for close to three decades, all may not be seemingly well with the family of gadolinium compounds. If the first signs of violations ofin relation to gadolinium-based contrast agents (GBCAs) appeared in the millennium year with the first published report of skin fibrosis in patients with compromised renal function, the causal relationship between the development of nephrogenic systemic fibrosis (NSF) and GBCAs, first proposed by two European groups in 2006, further precluded their use in renocompromised patients. The toxicity, pharmacokinetics, and pharmacodynamics of GBCAs, however, has come under hawk-eyed scrutiny with recent reports that gadolinium tends to deposit cumulatively in the brain of patients with normal hepatobiliary function and intact blood-brain barrier. While the jury on the long-term hazard significance of this critical scientific finding is still out, the use of GBCAs must be guided by due clinical diligence, avoidance of repeated doses, and preferring GBCAs with the best safety profiles.

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PMID: 

Biometals. 2016 06 ;29(3):365-76. Epub 2016 Apr 6. PMID: 27053146

Abstract Title: 

Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms.

Abstract: 

Gadolinium chelates are widely used as contrast media for magnetic resonance imaging. The approved gadolinium-based contrast agents (GBCAs) have historically been considered safe and well tolerated when used at recommended dosing levels. However, for nearly a decade, an association between GBCA administration and the development of nephrogenic systemic fibrosis (NSF) has been recognized in patients with severe renal impairment. This has led to modifications in clinical practices aimed at reducing the potential and incidence of NSF development. Newer reports have emerged regarding the accumulation of gadolinium in various tissues of patients who do not have renal impairment, including bone, brain, and kidneys. Despite the observations of gadolinium accumulation in tissues regardless of renal function, very limited clinical data regarding the potential for and mechanisms of toxicity is available. This significant gap in knowledge warrants retrospective cohort study efforts, as well as prospective studies that involve gadolinium ion (Gd(3+)) testing in patients exposed to GBCA. This review examines the potential biochemical and molecular basis of gadolinium toxicity, possible clinical significance of gadolinium tissue retention and accumulation, and methods that can limit gadolinium body burden.

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PMID: 

Invest Radiol. 2019 Aug ;54(8):453-463. PMID: 31265439

Abstract Title: 

Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent.

Abstract: 

OBJECTIVES: This preclinical study was devised to investigate potential cellular toxicity in human neurons induced by gadolinium-based contrast agents (GBCAs) used for contrast-enhanced magnetic resonance imaging (MRI). Neurons modeling a subset of those in the basal ganglia were tested, because the basal ganglia region is 1 of 2 brain regions that displays the greatest T1-dependent signal hyperintensity changes.METHODS: Eight GBCAs were tested. Dopaminergic neurons modeling a subset of those in the basal ganglia were differentiated from an established human neuroblastoma cell line and exposed to increasing concentrations of each agent for 7 days. The tested dosages ranged from clinically relevant concentrations measured in some autopsy patients who had received repeated injections of contrast for MRI, to higher concentrations to reveal dose-dependent toxicity trends. Cell death, mitochondrial membrane potential, mitochondrial oxidative capacity, and mitochondrial function measured by oxygen consumption were quantified in cells treated with each GBCA or the osmolality control mannitol and compared to untreated cells which served as a negative control.RESULTS: Mannitol caused no change from negative controls in any of the tests, at any concentration tested. For all GBCAs, cell death increased with exposure dose, with toxicity at clinically relevant doses for agents with lower kinetic stability. Reduction of mitochondrial membrane potential and oxidative respiratory function also generally mirrored the agents' structural kinetic stabilities, with greater impairment at lower concentration for the less stable agents.CONCLUSIONS: In human neurons modeling a subset of those in the basal ganglia, these results demonstrate a toxic effect of gadolinium-containing MRI contrast agents on mitochondrial respiratory function and cell viability. Toxicity increases as agent concentration increases and as the kinetic stability of the agent decreases.

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PMID: 

Physiol Meas. 2018 11 28 ;39(11):115008. Epub 2018 Nov 28. PMID: 30485255

Abstract Title: 

Self-identified gadolinium toxicity: comparison of gadolinium in bone and urine to healthy gadolinium-based contrast agent exposed volunteers.

Abstract: 

OBJECTIVE: To report additional gadolinium bone and urine data that can contribute to gaps in knowledge with respect to gadolinium uptake and retention in the body.APPROACH: In vivo measurements of gadolinium retention in the tibia bone were performed on individuals self-identified as exhibiting symptoms of gadolinium toxicity as a result of receiving GBCA, as well as on control individuals. Gadolinium urine measurements for controls, symptomatic exposed, and non-symptomatic exposed were conducted through Mayo Medical Laboratories.MAIN RESULTS: Gadolinium bone concentration in the exposed group is significantly higher than the control group (p

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PMID: 

Invest Radiol. 2019 Sep 9. Epub 2019 Sep 9. PMID: 31503081

Abstract Title: 

Gadolinium Retention in Erythrocytes and Leukocytes From Human and Murine Blood Upon Treatment With Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging.

Abstract: 

OBJECTIVES: Being administered intravenously, the tissue that gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging mostly encounter is blood. Herein, it has been investigated how much Gd is internalized by cellular blood components upon the in vitro incubation of GBCAs in human blood or upon intravenous administration of GBCAs to healthy mice. We report results that show how the superb sensitivity of inductively coupled plasma-mass spectrometry (ICP-MS) allows the detection of very tiny amounts of GBCAs entering red blood cells (RBCs) and white blood cells (WBCs). This finding may introduce new insights in the complex matter relative to excretion and retention pathway of administered GBCAs.MATERIALS AND METHODS: The study was tackled by 2 independent approaches. First, human blood was incubated in vitro with 5 mM of GBCAs (gadoteridol, gadobenate dimeglumine, gadodiamide, and gadopentetate dimeglumine) for variable times (30 minutes, 1 hour, 2 hours, and 3 hours) at 37°C. Then, blood cell components were isolated by using the Ficoll Histopaque method, washed 3 times, mineralized, and analyzed by ICP-MS for total Gd quantification. Furthermore, blood components derived from human blood incubated with gadodiamide or gadoteridol underwent UPLC-MS (ultra performanceliquid chromatography-mass spectrometry) analysis for determination of the amount of intact Gd-DTPA-BMA and Gd-HPDO3A. Second, the distribution of Gd in the blood components of healthy CD-1 mice was administered intravenously with a single dose (1.2 mmol/kg) of gadodiamide or gadoteridol. Blood samples were separated and processed at different time points (24 hours, 48 hours, 96 hours, and 10 days after GBCA administration). As for human blood, ICP-MS quantification of total Gd and UPLC-MS determination of the amount of intact GBCAs were carried out.RESULTS: The amount of Gd taken up by RBCs and WBCs was well detectable by ICP-MS. The GBCAs seem to be able to cross the membrane by diffusion (RBCs) or, possibly, by macropinocytosis (WBCs). Ex vivo studies allowed it to be established that the structure of the different GBCAs were not relevant to determine the amount of Gd internalized in the cells. Although the amount of Gd steadily decreases over time in gadoteridol-labeled cells, in the case of gadodiamide, the amount of Gd in the cells does not decrease (even 10 days after the administration of the GBCA). Moreover, while gadoteridol maintains its structural integrity upon cellular uptake, in the case of gadodiamide, the amount of intact complex markedly decreases over time.CONCLUSIONS: The detection of significant amounts of Gd in RBCs and WBCs indicates that GBCAs can cross blood cell membranes. This finding may play a role in our understanding of the processes that are at the basis of Gd retention in the tissues of patients who have received the administration of GBCAs.

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PMID: 

Anat Rec (Hoboken). 2019 Sep 11. Epub 2019 Sep 11. PMID: 31509337

Abstract Title: 

Trace element concentration changes in brain tumors: a review.

Abstract: 

Trace elements have been implicated in cancer, since the levels differ between cancerous and non-cancerous tissue, different cancer types, and different malignancy grades. However, few studies have been conducted on trace element concentrations in brain tumors. Thus, this study aims to review the available literature on trace element changes related to brain tumors, and to identify gaps in the literature. A literature search was done on Google Scholar and PubMed from their start date to January 2018, using terms related to trace element concentration and brain tumors. All brain tumor types were included, and articles could be published in any year. From this search, only 11 articles on this topic could be found. Tumors had significantly higher concentrations of arsenic, thorium, lanthanum, lutetium, cerium, and gadolinium compared to control brain samples. Compared to adjacent tissue, tumor tissue indicated increased magnesium, decreased copper, and contradicting results for zinc. Furthermore, the higher the malignancy grade, the lower the calcium, cadmium, iron, phosphorus and sulfur concentration, and the higher the mercury, manganese, lead, and zinc concentrations. In conclusion, altered trace element levels differ amongst different tumor types, as well as malignancy grades. Consequently, it is impossible to compare data from these studies, and available data is still considerably inconclusive. Ideally, future studies should have a sufficient samples size, compare different tumor types, and compare tumors with adjacent healthy tissue as well as with samples from unaffected matched brains. This article is protected by copyright. All rights reserved.

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PMID: 

Rehabil Nurs. 2019 Sep/Oct;44(5):254-262. PMID: 31479435

Abstract Title: 

Thermotherapy Combined With Therapeutic Exercise Improves Muscle Strength and Depression in Patients With Ischemic Stroke.

Abstract: 

PURPOSE: The study examined the effect of home-based thermotherapy combined with therapeutic exercise on muscle strength and depression in patients with ischemic stroke via a weekly evaluation over 4 weeks.DESIGN/METHODS: A quasi-experimental, pre-/posttest research design without a control group was employed. A total of 22 patients participated. Self-reported daily logs were used to evaluate intervention adherence over the study period. The manual muscle testing and Aphasic Depression Rating Scale were administered at baseline and weekly for 4 weeks.RESULTS: Muscle strength in both the upper and lower limbs significantly increased (p

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PMID: 

Medicina (Kaunas). 2019 Sep 2 ;55(9). Epub 2019 Sep 2. PMID: 31480778

Abstract Title: 

Physical Activity and the Occurrence of Postnatal Depression-A Systematic Review.

Abstract: 

During pregnancy and the postnatal period many changes occur in a woman's body, both in mental and physical spheres. The birth of a child and a new role-of a mother-can sometimes be associated with numerous negative emotions, uncertainty, fear, anxiety, disgust, depression, or sadness. In the puerperium period, the development of baby blues or postpartum depression may occur. Postpartum depression develops within one month of childbirth and may last up to one year. Depressive disorders that may develop in a young mother affect both her and the newborn's health. That is why it is so important to try to search for factors that could significantly reduce the likelihood of developing depression in this period. The study aims at assessing the relationship between physical activity during pregnancy and puerperium or in the postpartum and the development of postnatal depression.A review of the literature was carried out in the Medline-PubMed database. The search terms were"pregnancy"AND"physical activity AND postpartum depression". The study included only English-language publications published in the period 2000-2018.A total of 216 references were found. After establishing the inclusion and exclusion criteria based on the analysis of titles and abstracts, 173 articles were excluded from the review. A total of 43 publications were read in full. Finally, 16 articles were included in the review. It was shown that regular physical activity during pregnancy, pregnancy, and puerperium, or in the postnatal period itself as compared to inactivity, reduces the risk of developing depression in pregnant women and after the birth of a child.Physical activity can be an essential factor in the prevention of depressive disorders of women in the postnatal period.

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PMID: 

J Exerc Rehabil. 2019 Jun ;15(3):383-391. Epub 2019 Jun 30. PMID: 31316930

Abstract Title: 

Treadmill exercise ameliorates nicotine withdrawal-induced symptoms.

Abstract: 

Nicotine withdrawal symptoms comprise insomnia, depression, anxiety, attention disorders, and increased craving. We evaluated the ameliorating effect of treadmill exercise on nicotine withdrawal symptoms. The rats in the nicotine withdrawal groups received subcutaneous injection with 6-mg/kg nicotine hydrogen tartrate salt for 17 days. And then, the injection of nicotine hydrogen tartrate salt was stopped next for 2 weeks. The rats in the exercise groups performed treadmill running once a day, 5 days per week, for 31 days. In the present results, activity was decreased and anxiety-like behavior was observed in the nicotine withdrawal rats. Treadmill running increased activity and ameliorated anxiety-like behavior in the nicotine-withdrawal rats. Expressions of tryptophan hydroxylase (TPH) and 5-hydroxytryptamine (5-HT) in the dorsal raphe were decreased in the nicotine withdrawal rats, in contrast, treadmill running increased TPH and 5-HT expressions. Impaired short-term memory and deteriorated spatial learning ability were observed in the nicotine withdrawal rats, in contrast, treadmill running ameliorated impairment of short-term memory and spatial learning ability. Expressions of brain-derived neurotrophic factor and tyrosine kinase B (TrkB) were decreased in the nicotine withdrawal rats, in contrast, treadmill running increased brain-derived neurotrophic factor and TrkB expressions. The numbers of the doublecortin (DCX)-positive cells and 5-bromo-2'-deoxyuridine (BrdU)-positive cells in the dentate gyrus were suppressed in the nicotine withdrawal rats, in contrast, treadmill running enhanced the numbers of DCX-positive cells and BrdU-positive cells. The present study demonstrate that treadmill exercise ameliorated nicotine withdrawal-induced anxiety, depression, and memory impairment.

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PMID: 

J Trace Elem Electrolytes Health Dis. 1987 Dec ;1(2):69-72. PMID: 2856571

Abstract Title: 

Differences in plasma and tissue aluminum concentrations due to different aluminum-containing drugs in patients with renal insufficiency and with normal renal function.

Abstract: 

The gastrointestinal absorption of aluminum from orally administered aluminum-containing drugs is well documented. Retention of the absorbed aluminum leads to elevated levels of this metal in the tissue of patients with renal failure. We studied two groups of dialysis patients who had received equal amounts of the different aluminum-containing phosphate-binders Aludrox and Antiphosphat. It has recently been shown that Antiphosphat releases only a few aluminum ions in an environment of low pH. Consistent with this finding, we found the aluminum levels to be significantly higher in the plasma, bone, and hair of patients who had received Aludrox as phosphate binder. Subjects with normal renal function excreted most of the ingested and absorbed aluminum. No data are available concerning the tissue load of the element in these subjects. We studied two groups of patients with normal renal function who had received antacid drugs prior to neurosurgery on a brain tumor. The first group of patients were treated with an aluminum-rich antacid (Maalox 70); the other group received an aluminum-poor drug (magaldrate) for 10 days prior to the operation. Analysis of the brain-tissue removed revealed twofold higher aluminum levels in the patients who had received Maalox 70. These results indicate that administration of aluminum-containing drugs leads to a tissue load of aluminum in patients with an impaired renal function as well as in those with a normal function. The extent of the aluminum load depends on the aluminum content and the liberation rate of the drug.

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