PMID: 

Magn Reson Imaging. 2016 Dec ;34(10):1394-1398. Epub 2016 Sep 28. PMID: 27693607

Abstract Title: 

Gadolinium toxicity and treatment.

Abstract: 

Gadolinium based contrast agents (GBCAs) play an important role in the diagnostic evaluation of many patients. The safety of these agents has been once again questioned after gadolinium deposits were observed and measured in brain and bone of patients with normal renal function. This retention of gadolinium in the human body has been termed"gadolinium storage condition". The long-term and cumulative effects of retained gadolinium in the brain and elsewhere are not as yet understood. Recently, patients who report that they suffer from chronic symptoms secondary to gadolinium exposure and retention created gadolinium-toxicity on-line support groups. Their self-reported symptoms have recently been published. Bone and joint complaints, and skin changes were two of the most common complaints. This condition has been termed"gadolinium deposition disease". In this review we will address gadolinium toxicity disorders, from acute adverse reactions to GBCAs to gadolinium deposition disease, with special emphasis on the latter, as it is the most recently described and least known.

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PMID: 

Apoptosis. 2017 Feb ;22(2):188-199. PMID: 27770270

Abstract Title: 

Gadolinium induced effects on mammalian cell motility, adherence and chromatin structure.

Abstract: 

The toxicity of gadolinium is reduced by chelating agents that render this heavy metal into contrast complexes used for medical magnetic resonance imaging. However, the dissociation of gadolinium chelates is known to generate Gdions, the cellular toxicity of which has not been tested in details. The cytotoxic effects of Gd(III) ions were evaluated by monitoring the proliferation, measuring the cellular motility and following chromatin changes in various cell lines upon Gdtreatment. Measurements applied long-term scanning microscopy and a perfusion platform that replaced the medium with test solutions, bypassed physical contact with the cell culture during experiments, and provided uninterrupted high time-resolution time-lapse photomicrography for an extended period of time. Genotoxicity specific chromatin changes characteristic to Gd(III) were distinguished in human skin keratinocytes (HaCaT), human limbal stem cells (HuLi), colorectal adenocarcinoma (CaCO), murine squamous carcinoma (SCC) and Indian muntjac (IM) cell lines. Characteristic features of Gd(III) toxicity were: loss of cellular motility, irreversible attachment of cells to the growth surface and cell death. Injury-specific chromatin changes manifested at micromolar Gdconcentrations as premature chromatin condensation and highly condensed sticky chromatin patches. Gd(III) concentration- and cell type-dependent reduction of normal adherence, as well as premature chromatin condensation confirmed apoptosis. The risk related to the release of toxic Gdions from gadolinium complexes and their effects on mono- and multi-layer cellular barriers have to be reconsidered when these chelated complexes are used as contrasting agents especially in relation to possible blood-brain barrier damages.

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PMID: 

Nutr Metab Cardiovasc Dis. 2019 Jun ;29(6):633-638. Epub 2019 Feb 28. PMID: 30956026

Abstract Title: 

Exposure to solar ultraviolet radiation limits diet-induced weight gain, increases liver triglycerides and prevents the early signs of cardiovascular disease in mice.

Abstract: 

BACKGROUND AND AIMS: Sunlight exposure is associated with a number of health benefits including protecting us from autoimmunity, cardiovascular disease, obesity and diabetes. Animal studies have confirmed that ultraviolet (UV)-B radiation, independently of vitamin D, can limit diet-induced obesity, metabolic syndrome and atherosclerosis. The aim of this study is to investigate whether exposure to the UV radiation contained in sunlight impacts on these disease parameters.METHODS AND RESULTS: We have trialled an intervention with solar UV in obese and atherosclerosis-prone mice. We have discovered that solar-simulated UV can significantly limit diet-induced obesity and reduce atheroma development in mice fed a diet high in sugar and fat. The optimal regime for this benefit was exposure once a week to solar UV equivalent to approximately 30 min of summer sun. Exposure to this optimal dose of solar UV also led to a significant increase in liver triglycerides which may protect the liver from damage.CONCLUSION: Our results show that the UV contained in sunlight has the potential to prevent and treat chronic disease at sites distant from irradiated skin. A major health challenge going forward will be to harness the power of the sun safely, without risking an increase in skin cancers.

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PMID: 

JAMA Pediatr. 2013 Sep ;167(9):870-2. PMID: 23856981

Abstract Title: 

Effect of routine vaccination on aluminum and essential element levels in preterm infants.

Abstract: 

Parenteral feedings containing more than 4 to 5 μg/kg/d of aluminum have been shown to result in neurodevelopmental delay in preterm infants.1 However, an infant at the 2-month checkup receives multiple aluminum-containing vaccines that in combination may have as high as 1225 μg of intramuscular aluminum; this is a much higher intramuscular aluminum dose than the safely recommended intravenous aluminum dose.2 Our first objective was to measure prevaccine and postvaccine levels of aluminum in preterm infants, a population at higher risk of aluminum neurotoxic effects. Our second objective was to measure prevaccine and postvaccine levels of
essential elements (EE). Inflammation from trauma can cause declines in serum levels of specific EE such as zinc and selenium3-5; there may be similar EE perturbations secondary to vaccination-induced inflammation.

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PMID: 

Acta Biomater. 2017 01 15 ;48:521-529. Epub 2016 Nov 11. PMID: 27845277

Abstract Title: 

Gadolinium accumulation in organs of Sprague-Dawley® rats after implantation of a biodegradable magnesium-gadolinium alloy.

Abstract: 

: Biodegradable magnesium implants are under investigation because of their promising properties as medical devices. For enhancing the mechanical properties and the degradation resistance, rare earth elements are often used as alloying elements. In this study Mg10Gd pins were implanted into Sprague-Dawley® rats. The pin volume loss and a possible accumulation of magnesium and gadolinium in the rats' organs and blood were investigated in a long-term study over 36weeks. The results showed that Mg10Gd is a fast disintegrating material. Already 12weeks after implantation the alloy is fragmented to smaller particles, which can be found within the intramedullary cavity and the cortical bones. They disturbed the bone remodeling until the end of the study. The results concerning the elements' distribution in the animals' bodies were even more striking, since an accumulation of gadolinium could be observed in the investigated organs over the whole time span. The most affected tissue was the spleen, with up to 3240μgGd/kg wet mass, followed by the lung, liver and kidney (up to 1040, 685 and 207μgGd/kg). In the brain, muscle and heart, the gadolinium concentrations were much smaller (less than 20μg/kg), but an accumulation could still be detected. Interestingly, blood serum samples showed no accumulation of magnesium and gadolinium. This is the first time that an accumulation of gadolinium in animal organs was observed after the application of a gadolinium-containing degradable magnesiumimplant. These findings demonstrate the importance of future investigations concerning the distribution of the constituents of new biodegradable materials in the body, to ensure the patients' safety.STATEMENT OF SIGNIFICANCE: In the last years, biodegradable Mg alloys are under investigation due to their promising properties as orthopaedic devices used for bone fracture stabilization. Gadolinium as Rare Earth Element enhances the mechanical properties of Mg-Gd alloys but its toxicity in humans is still questionable. Up to now, there is no study investigating the elements' metabolism of a REE-containing Magnesium alloy in an animal model. In this study, we examined the gadolinium distribution and accumulation in rat organs during the degradation of Mg10Gd. Our findings showed that Gd is accumulating in the animal organs, especially in spleen, liver and kidney. This study is of crucial benefit regarding a safe application of REE-containing Magnesium alloys in humans.

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PMID: 

Vaccine. 2011 Nov 28 ;29(51):9538-43. Epub 2011 Oct 11. PMID: 22001122

Abstract Title: 

Updated aluminum pharmacokinetics following infant exposures through diet and vaccination.

Abstract: 

Aluminum is a ubiquitous element that is released naturally into the environment via volcanic activity and the breakdown of rocks on the earth's surface. Exposure of the general population to aluminum occurs primarily through the consumption of food, antacids, and buffered analgesics. Exposure to aluminum in the general population can also occur through vaccination, since vaccines often contain aluminum salts (frequently aluminum hydroxide or aluminum phosphate) as adjuvants. Because concerns have been expressed by the public that aluminum in vaccines may pose a risk to infants, we developed an up-to-date analysis of the safety of aluminum adjuvants. Keith et al. [1] previously analyzed the pharmacokinetics of aluminum for infant dietary and vaccine exposures and compared the resulting body burdens to those based on the minimal risk levels (MRLs) established by the Agency for Toxic Substances and Disease Registry. We updated the analysis of Keith et al. [1] with a current pediatric vaccination schedule [2]; baseline aluminum levels at birth; an aluminum retention function that reflects changing glomerular filtration rates in infants; an adjustment for the kinetics of aluminum efflux at the site of injection; contemporaneous MRLs; and the most recent infant body weight data for children 0-60 months of age [3]. Using these updated parameters we found that the body burden of aluminum from vaccines and diet throughout an infant's first year of life is significantly less than the corresponding safe body burden of aluminum modeled using the regulatory MRL. We conclude that episodic exposures to vaccines that contain aluminum adjuvant continue to be extremely low risk to infants and that the benefits of using vaccines containing aluminum adjuvant outweigh any theoretical concerns.

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PMID: 

Life Sci. 2019 Aug 26:116794. Epub 2019 Aug 26. PMID: 31465731

Abstract Title: 

Crocin attenuates lung inflammation and pulmonary vascular dysfunction in a rat model of bleomycin-induced pulmonary fibrosis.

Abstract: 

Amongst the various forms of lung injury; pulmonary fibrosis remains the most intricate form with limited therapeutic options to both the patient and the physicians. Bleomycin (BLM) is a chemotherapeutic agent used for the treatment of various carcinomas; however, its therapeutic value is significantly limited by its associated pulmonary fibrosis. The current study highlights the prominent antioxidant, anti-inflammatory and anti-fibrotic effect of crocin against BLM-induced pulmonary fibrosis. Intratracheal BLM instillation induced significant biochemical, structural, functional and vascular pulmonary injury. BLM instillation increased oxidant load with quenching of antioxidant defenses together with increase inflammatory and fibrotic cytokines expression. Crocin significantly attenuated BLM-induced lung injury and its effect was comparable to the standard anti-fibrotic; halofuginone. The observed anti-inflammatory and anti-fibrotic and antioxidant impacts are thought to be embroiled in the therapeutic impacts of crocin. Down-regulation of TLR4, IL-10 expression is the major pathway involved in the observed anti-inflammatory effects and finally, down-regulation of tissue expression of TNF-α and TGF-β1 is the major pathways implicated in the observed anti-fibrotic activities and modulation of Nrf2 and HO-1 pathways is the main mechanism involved in the observed antioxidant effects.

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PMID: 

Eur J Pharmacol. 2019 Sep 3 ;862:172640. Epub 2019 Sep 3. PMID: 31491407

Abstract Title: 

Crocin ameliorates chronic obstructive pulmonary disease-induced depression via PI3K/Akt mediated suppression of inflammation.

Abstract: 

Clinical studies have indicated the co-occurrence of chronic obstructive pulmonary disease (COPD) and psychiatric disorders, for example, comorbid depression. However, the underlying mechanism is rarely addressed. The present study aimed to investigate the mechanism of COPD-induced depression and the psychological and physiological effects of crocin, an active constituent of Crocus sativus L. C57BL/6 mice were randomly exposed to cigarette smoke for 7 weeks to establish COPD animal model. Crocin (50 mg/kg), Dexamethasone (2 mg/kg) and IGF-1 (2 mg/kg) were respectively injected to mice once a day. The FEV/FVC ratio and the mean alveolus area of lung tissue demonstrated the COPD model was successfully established by cigarette smoke. Crocin administration significantly reversed markers of depression [loss of body weight, sucrose preference, and elevation of immobile time in tail-suspension tests (TST) and in forced swimming tests (FST)]. Besides, crocin treatment significantly inhibited the numbers of inflammatory cells (macrophages, neutrophils, and lymphocytes), suppressed the infiltration of peribronchial inflammatory cells, and reduced the concentration of proinflammatory cytokines in bronchoalveolar lavage (BAL) fluid and lung tissue. Crocin also reduced proinflammatory cytokines in the hippocampus. In exploring associated mechanisms, we discovered that crocin blunted cigarette smoke-induced IκB phosphorylation and degradation, and NF-κBp65 nuclear translocation. IGF-1, an activator of PI3K, abrogated the effect of crocin against cigarette smoke-induced activation of the NF-κB pathway. Together, these results showed that an inflammatory mechanism might be involved in the pathogenesisof COPD with comorbid depression. Crocin exhibited significant effects through the regulation of PI3K/Akt-mediated inflammatory pathways.

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PMID: 

Invest Radiol. 2019 02 ;54(2):61-71. PMID: 30394964

Abstract Title: 

Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone Tissues?: A Comparative Gadoterate Versus Gadodiamide Study in Juvenile and Adult Rats.

Abstract: 

OBJECTIVES: The main objective of the study was to assess the effect of age on target tissue total gadolinium (Gd) retention after repeated administration of gadodiamide (linear) or gadoterate (macrocyclic) Gd-based contrast agent (GBCA) in rats. The secondary objective was to assess the potential developmental and long-term consequences of GBCA administration during neonatal and juvenile periods.MATERIALS AND METHODS: A total of 20 equivalent human clinical doses (cumulated dose, 12 mmol Gd/kg) of either gadoterate or gadodiamide were administered concurrently by the intravenous route to healthy adult and juvenile rats. Saline was administered to juvenile rats forming the control group. In juvenile rats, the doses were administered from postnatal day 12, that is, once the blood-brain barrier is functional as in humans after birth. The tests were conducted on 5 juvenile rats per sex and per group and on 3 adult animals per sex and per group. T1-weighted magnetic resonance imaging of the cerebellum was performed at 4.7 T during both the treatment and treatment-free periods. Behavioral tests were performed in juvenile rats. Rats were euthanatized at 11 to 12 weeks (ie, approximately 3 months) after the last administration. Total Gd concentrations were measured in plasma, skin, bone, and brain by inductively coupled plasma mass spectrometry. Cerebellum samples from the juvenile rats were characterized by histopathological examination (including immunohistochemistry for glial fibrillary acidic protein or GFAP, and CD68). Lipofuscin pigments were also studied by fluorescence microscopy. All tests were performed blindly on randomized animals.RESULTS: Transient skin lesions were observed in juvenile rats (5/5 females and 2/4 males) and not in adult rats having received gadodiamide. Persisting (up to completion of the study) T1 hyperintensity in the deep cerebellar nuclei (DCNs) was observed only in gadodiamide-treated rats. Quantitatively, a slightly higher progressive increase in the DCN/brain stem ratio was observed in adult rats compared with juvenile rats, whereas no difference was noted visually. In all tissues, total Gd concentrations were higher (10- to 30-fold higher) in the gadodiamide-treated groups than in the gadoterate groups. No age-related differences were observed except in bone marrow where total Gd concentrations in gadodiamide-treated juvenile rats were higher than those measured in adults and similar to those measured in cortical bone tissue. No significant treatment-related effects were observed in histopathological findings or in development, behavior, and biochemistry parameters. However, in the elevated plus maze test, a trend toward an anxiogenic effect was observed in the gadodiamide group compared with other groups (nonsignificant). Moreover, in the balance beam test, a high number of trials were excluded in the gadodiamide group because rats (mainly males) did not completely cross the beam, which may also reflect an anxiogenic effect.CONCLUSIONS: No T1 hyperintensity was observed in the DCN after administration of the macrocyclic GBCA gadoterate regardless of age as opposed to administration of the linear GBCA gadodiamide. Repeated administration of gadodiamide in neonatal and juvenile rats resulted in similar total Gd retention in the skin, brain, and bone to that in adult rats with sex having no effect, whereas Gd distribution in bone marrow was influenced by age. Further studies are required to assess the form of the retained Gd and to investigate the potential risks associated with Gd retention in bone marrow in juvenile animals treated with gadodiamide. Regardless of age, total Gd concentration in the brain and bone was 10- to 30-fold higher after administration of gadodiamide compared with gadoterate.

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PMID: 

Med Hypotheses. 2019 Aug ;129:109240. Epub 2019 May 20. PMID: 31371082

Abstract Title: 

The gadolinium hypothesis for fibromyalgia and unexplained widespread chronic pain.

Abstract: 

Fibromyalgia (FM) is a chronic, painful, heterogeneous, and common disorder carrying a substantial socio-economical burden. It lacks effective cures and its aetiology is still unknown. There exists evidence for central and peripheral neurological contribution to the symptoms but grasping the real source of abnormal nervous system sensitization remains an ongoing challenge. There exists an association between an injury/trauma and the onset of the symptoms, but a causal relationship has not been yet sufficiently supported by scientific evidence. I postulate a role for gadolinium-based contrast agents and retention of gadolinium in the body. This conjecture breaks the hypothesis of a direct role for a physical injury/trauma per se in favour of an indirect one by the subsequent diagnostic procedures. It creates a new link between retention of gadolinium in the body and painful conditions as FM and unexplained chronic widespread pain reported after a trauma, surgery, or medical illness. Experimental evidence demonstrates possible retention of gadolinium species in human body, still lacking conclusive answers on their pathological consequences. Notwithstanding, there exist some initial data that report unexplained chronic widespread pain and symptoms of FM in those patients: they are suggestive for pathological consequences associated with gadolinium retention. Besides clear compelling symptoms overlapping, biochemical findings are provided to sustain the hypothesis of a role for gadolinium in the disease process focusing on neurotransmitters, endogenous metal cations, cytokines, and muscle tissue. Experimental findings strongly support the hypothesis of impairment at the cellular, intracellular, and systemic levels in FM. And these data are highly compatible with collateral effects associated with the interference of the gadolinium ion and its pharmaceutical chelates into biochemical pathways in vivo. The hypothesis presented in this article, along with the support of scientific evidence, links FM and unexplained chronic widespread pain reported after a trauma, surgery, or medical illness to retention of gadolinium in the body. If the hypothesis is confirmed, it could improve diagnosis and prevention, while providing a ground for development of new treatments.

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