The Impact of Long-Term Clinoptilolite Administration on the Concentration Profile of Metals in Rodent Organisms.

Heavy metals are dangerous systemic toxicants that can induce multiple organ damage, primarily by inducing oxidative stress and mitochondrial damage. Clinoptilolite is a highly porous natural mineral with a magnificent capacity to eliminate metals from living organisms, mainly by ion-exchange and adsorption, thus providing detoxifying, antioxidant and anti-inflammatory medicinal effects. The in vivo efficiency and safety of the oral administration of clinoptilolite in its activated forms, tribomechanically activated zeolite (TMAZ) and Panaceo-Micro-Activated (PMA) zeolite, as well as the impact on the metallic biodistribution, was examined in healthy female rats. Concentration profiles of Al, As, Cd, Co, Pb, Ni and Sr were measured in rat blood, serum, femur, liver, kidney, small and large intestine, and brain using inductively coupled plasma mass spectrometry (ICP-MS) after a 12-week administration period. Our results point to a beneficial effect of clinoptilolite materials on the concentration profile of metals in female rats supplemented with the corresponding natural clinoptilolite materials, TMAZ and PMA zeolite. The observed decrease of measured toxicants in the kidney, femur, and small and large intestine after three months of oral intake occurred concomitantly with their most likely transient release into the bloodstream (serum) indicative of a detoxification process.

Efficacy and Safety of Pulsed Radiofrequency as a Method of Dorsal Root Ganglia Stimulation in Patients with Neuropathic Pain: A Systematic Review.

OBJECTIVE: Pulsed radiofrequency (PRF) is a nonablative pain treatment that uses radiofrequency current in short high-voltage bursts, resulting in interruption of nociceptive afferent pathways. We conducted a systematic review with the aim to create a synthesis of evidence about the efficacy and safety of PRF applied to the dorsal root ganglion (DRG) for the treatment of neuropathic pain. METHODS: We searched MEDLINE, CINAHL, Embase, and PsycINFO through January 8, 2019, as well as ClinicalTrials.gov and the clinical trial register of the World Health Organization. All study designs were eligible. We assessed risk of bias using the Cochrane tool for randomized controlled trials and the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I). We assessed level of evidence using the Oxford tool and quality of evidence with GRADE. RESULTS: We included 28 studies with participants suffering from lumbosacral, cervical, or thoracic radicular pain, post-herpetic neuralgia, neuropathicbone pain in cancer patients, or carpal tunnel syndrome. Only five studies were randomized controlled trials (RCTs), while others were of nonrandomized designs, predominantly before and after comparisons. A total of 991 participants were included, with a median number (range) of 31 (1-101) participants. Only 204 participants were included in the RCTs, with a median number (range) of 38 (23-62) participants. The overall quality of evidence was low, as the majority of the included studies were rated as evidence level 4 or 5. The quality of evidence was very low. CONCLUSIONS: Evidence about the efficacy and safety of PRF of the DRG for the treatment of neuropathic pain is based mainly on results from very small studies with low evidence quality. Current research results about the benefits of PRF of the DRG for the treatment of neuropathic pain should be considered preliminary and confirmed in high-quality RCTs with sufficient numbers of participants.

Efficacy and safety of pulsed radiofrequency as a method of dorsal root ganglia stimulation for treatment of non-neuropathic pain: a systematic review.

BACKGROUND: We systematically reviewed the evidence on the efficacy and safety of dorsal root ganglion (DRG) targeted pulsed radiofrequency (PRF) versus any comparator for treatment of non-neuropathic pain. METHODS: We searched MEDLINE, CINAHL, Embase, PsycINFO, clinicaltrials.gov and WHO clinical trial register until January 8, 2019. All study designs were eligible. Two authors independently conducted literature screening. Primary outcomes were pain intensity and serious adverse events (SAEs). Secondary outcomes were any other pain-related outcome and any other safety outcome that was reported. We assessed the risk of bias using the Cochrane tool and Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I). We conducted narrative evidence synthesis and assessed the conclusiveness of included studies regarding efficacy and safety. RESULTS: We included 17 studies with 599 participants, which analyzed various pain syndromes. Two studies were randomized controlled trials; both included participants with low back pain (LBP). Non-randomized studies included patients with the following indications: LBP, postsurgical pain, pain associated with herpes zoster, cervicogenic headache, complex regional pain syndrome type 1, intractable vertebral metastatic pain, chronic scrotal and inguinal pain, occipital radiating pain in rheumatoid arthritis and chronic migraine. In these studies, the PRF was usually initiated after other treatments have failed. Eleven studies had positive conclusive statements (11/17) about efficacy; the remaining had positive inconclusive statements. Only three studies provided conclusiveness of evidence statements regarding safety - two indicated that the evidence was positive conclusive, and one positive inconclusive. The risk of bias was predominantly unclear in randomized and serious in non-randomized studies. CONCLUSION: Poor quality and few participants characterize evidence about benefits and harms of DRG PRF in patients with non-neuropathic pain. Results from available studies should only be considered preliminary. Not all studies have reported data regarding the safety of the intervention, but those that did, indicate that the intervention is relatively safe. As the procedure is non-destructive and early results are promising, further comparative studies about PRF in non-neuropathic pain syndromes would be welcomed.

Neuromodulation with electrical field stimulation of dorsal root ganglion in various pain syndromes: a systematic review with focus on participant selection.

OBJECTIVE: We conducted a systematic review about patient selection, efficacy, and safety of neuromodulation with electrical field stimulation (EFS) of dorsal root ganglion (DRG) in various painful conditions. We also analyzed conclusion statements as well as conflict of interest and financing of the included studies. METHODS: All study designs were eligible for inclusion. We searched MEDLINE, CINAHL, Embase, PsycINFO, and clinical trial registries until September 7, 2018. We assessed risk of bias by using Cochrane tool for randomized controlled trials (RCTs). RESULTS: Among the 29 included studies, only one was RCT, majority being case series and case reports. The evidence is based on studies with small number of participants (median: 6, range 1-152) with various painful conditions. Neuromodulation with EFS of DRG was mostly performed in participants who have failed other treatment modalities. Most of the authors of the included studies reported positive, but inconclusive, evidence regarding efficacy of neuro-modulation with EFS of DRG. Meta-analysis was not possible since only one RCT was included. CONCLUSION: Available evidence suggest that neuromodulation with EFS of DRG may help highly selected participants with various pain syndromes, who have failed to achieve adequate pain relief with other pharmacological and nonpharmacological interventions. However, these findings should be confirmed in high-quality RCTs with sufficient numbers of participants.

Changes in expression of special AT-rich sequence binding protein 1 and phosphatase and tensin homologue in kidneys of diabetic rats during ageing.

Background: Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM). We studied the expression of special AT-rich sequence binding protein 1 (SATB1) and phosphatase and tensin homologue (PTEN) in the kidneys of diabetic rats during ageing. Methods: Male Sprague Dawley rats were injected with 55 mg/kg streptozotocin (STZ) (DM group) or with citrate buffer (control group). Kidneys were collected after 2 weeks, 6 months and 12 months, and were analysed in three different kidney structures: glomeruli, proximal (PCT) and distal convoluted tubules (DCT). Sections were stained immunohistochemically, using SATB1 and PTEN. Results: Significant differences in marker expression were observed after 2 weeks, with higher SATB1 expression and lower PTEN expression in diabetic rats. PTEN was more highly expressed in controls after 6 and 12 months. After 12 months, there was higher SATB1 expression in diabetic rats. In the glomeruli, control rats had higher PTEN expression, whereas diabetic rats had higher SATB1 expression, after 12 months. PTEN expression increased from 2 weeks to 12 months in both the PCT and DCT of control rats. SATB1 was expressed exclusively in the PCT of diabetic rats after 2 weeks, and its expression in the DCT was higher in controls. After 6 months, both the PCT and DCT showed higher SATB1 expression in diabetic rats. Conclusions: The major changes in expression of SATB1 and PTEN occur after 2 weeks of DM onset, particularly in the PCT, implying an early onset of pathophysiological changes in diabetic kidneys, which would normally occur with ageing. These findings help to contribute to our understanding of changes associated with DN and guide towards possible appropriate treatment modalities.

Changes in neurofilament 200 and tyrosine hydroxylase expression in the cardiac innervation of diabetic rats during aging.

Changes in sensory and sympathetic innervation during diabetes mellitus (DM) can be a predictor of arrhythmias, silent myocardial ischemia, and chronic heart failure, but knowledge about these changes is still unsatisfactory. We analyzed whether prolonged DM induces changes in density of sensory and sympathetic nerve terminals of rat's heart and whether it contributes to cardiomyopathy during aging. DM was induced by i/p injecting 55 mg/kg streptozotocin to male Sprague-Dawley rats, while a control group received a citrate buffer. DM in the rats was validated by measuring blood glucose level. Animals were sacrificed after 2 weeks, 2 months, 6 months, and 12 months. Five areas of cardiac sections were analyzed. Antibodies raised against tyrosine hydroxylase (TH) and neurofilament 200 kDa (NF 200) were used to detect sympathetic and sensory fibers. TH immunoreactive fiber density increased in DM groups 2 weeks after induction, reaching a peek after 2 months, while in the later stages of DM (6 and 12 months), there was no significant difference compared to control. NF 200 immunoreactive fiber density increased 2 weeks after induction compared to control. There was no consistent pattern of change during the given period in both the DM or control groups. In the DM group, we found thickening of the left ventricle wall (P<.05) as the sign of cardiomyopathy. Our findings suggest that hyperglycemia as a hallmark of DM in early stages can lead to proliferation of sympathetic and sensory nerve terminals. This finding can contribute to a better understanding of the occurrence of arrhythmias and silent myocardial ischemia in DM.

Electrical Stimulation of Dorsal Root Ganglion in the Context of Pain: A Systematic Review of In Vitro and In Vivo Animal Model Studies.

OBJECTIVE: Dorsal root ganglion (DRG) has recently emerged as an attractive target for neuromodulation therapy since primary sensory neurons and their soma in DRGs are important sites for pathophysiologic changes that lead to neuropathic pain. Our aim was to create evidence synthesis about the effects of electrical stimulation of DRG in the context of pain from in vitro and in vivo animal models, analyze methodology and quality of studies in the field. METHODS: For conducting systematic review we searched three data bases: MEDLINE, Embase and Web of Science. The quality of included studies was assessed with the Systematic Review Centre for Laboratory Animal Experimentation risk of bias tool for animal studies. The study was registered in the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies data base. RESULTS: We included six in vitro and eight in vivo animal studies. All included in vitro studies combined neurostimulation with substances or drugs and reported an improvement in pain-related parameters due to neurostimulation. Among in vivo studies, six used pulsed radiofrequency, while two used electrical field stimulation. All in vivo studies reported improvement in pain-related behavior following stimulation. Meta-analysis was not possible because of heterogeneity and missing data. The quality of included studies was suboptimal since all had an unclear risk of bias in multiple domains. CONCLUSIONS: Limited data from in vitro and in vivo animal studies indicate that electrical stimulation of DRG has a positive therapeutic effect in the context of pain-related outcomes. Further studies with a standardized methodological approach and outcomes will provide useful information about electrical stimulation of DRG in animal models.

Synthesis, characterization and in vitro biocompatibility assessment of a novel tripeptide hydrogelator, as a promising scaffold for tissue engineering applications.

We have synthesized and characterized a self-assembling tripeptide hydrogelator Ac-l-Phe-l-Phe-l-Ala-NH2. A series of experiments showed that the hydrogel material could serve as a stabile and biocompatible physical support as it improves the survival of HEK293T cells in vitro, thus being a promising biomaterial for use in tissue engineering applications.

Expression pattern of CYP24 in liver during ageing in long-term diabetes.

Association of liver calcitriol (active vitamin D metabolite) catabolism with osteomalacia during prolonged use of certain drugs was reported in several recent studies. To examine whether the increased calcitriol catabolism could be a potential link between ageing/diabetes mellitus (DM) and bone loss, we studied the dynamic of expression of CYP24, the main calcitriol catabolising enzyme in the liver of rats during ageing and a long-term experimental DM1. DM1 model was induced with intraperitoneally injected streptozotocin (STZ) (55mg/kg). Sprague-Dawley rats were sacrificed 6 and 12 months after the DM1 induction. The immunohistochemical analyses of CYP24 and transforming growth factor ß 1 (TGF-ß1) expression in the liver were performed. We found that ageing and long-term DM1 resulted in a significantly increased expression of CYP24 in hepatocytes, as well as in non-hepatocyte liver cells (Kupffer cells, hepatic stellate cells and sinusoidal endothelial cells). Ageing and long-term DM1 resulted in an increased expression of TGF-ß1 as well. Expression of CYP24 coexisted with the expression of TGF-ß1 in all types of hepatic cells. We concluded that liver has the capacity for an active vitamin D catabolism in different populations of liver cells, especially in sinusoidal endothelial cells, through an expression of CYP24. That capacity is substantially increased during ageing and long-term diabetes mellitus. Increased liver calcitriol catabolism could be one of the mechanisms of the bone metabolism impairment related to ageing and diabetes.

Superparamagnetic Fe3O4 Nanoparticles: Synthesis by Thermal Decomposition of Iron(III) Glucuronate and Application in Magnetic Resonance Imaging.

Monodisperse superparamagnetic Fe3O4 nanoparticles coated with oleic acid were prepared by thermal decomposition of Fe(III) glucuronate. The shape, size, and particle size distribution were controlled by varying the reaction parameters, such as the reaction temperature, concentration of the stabilizer, and type of high-boiling-point solvents. Magnetite particles were characterized by transmission electron microscopy (TEM), as well as electron diffraction (SAED), X-ray diffraction (XRD), dynamic light scattering (DLS), and magnetometer measurements. The particle coating was analyzed by atomic absorption spectroscopy (AAS) and attenuated total reflection (ATR) Fourier transform infrared spectroscopy (FTIR) spectroscopy. To make the Fe3O4 nanoparticles dispersible in water, the particle surface was modified with α-carboxyl-ω-bis(ethane-2,1-diyl)phosphonic acid-terminated poly(3-O-methacryloyl-α-D-glucopyranose) (PMG-P). For future practical biomedical applications, nontoxicity plays a key role, and the PMG-P&Fe3O4 nanoparticles were tested on rat mesenchymal stem cells to determine the particle toxicity and their ability to label the cells. MR relaxometry confirmed that the PMG-P&Fe3O4 nanoparticles had high relaxivity but rather low cellular uptake. Nevertheless, the labeled cells still provided visible contrast enhancement in the magnetic resonance image. In addition, the cell viability was not compromised by the nanoparticles. Therefore, the PMG-P&Fe3O4 nanoparticles have the potential to be used in biomedical applications, especially as contrast agents for magnetic resonance imaging.

Aging and a long-term diabetes mellitus increase expression of 1 α-hydroxylase and vitamin D receptors in the rat liver.

Diabetes mellitus (DM) is a metabolic disorder associated with serious liver complications. As a metabolic chronic disease, DM is very common in the elderly. Recent studies suggest ameliorating effects of vitamin D on metabolic and oxidative stress in the liver tissue in an experimental model of DM. The aim of this study was to investigate the expression of vitamin D receptors (VDRs) and 1α-hydroxylase, the key enzyme for the production of active vitamin D form (calcitriol) in the liver during long-term diabetes mellitus type 1 (DM1) in aging rats. We performed immunohistochemical analysis of liver expression of 1α-hydroxylase and VDRs during aging in long-term streptozotocin-induced DM1. 1α-Hydroxylase was identified in the monocyte/macrophage system of the liver. In addition to the nuclear expression, we also observed the expression of VDR in membranes of lipid droplets within hepatocytes. Aging and long-term DM1 resulted in significant increases in the number of 1α-hydroxylase immunoreactive cells, as well as the percentage of strongly positive VDR hepatocytes. In conclusion, the liver has the capacity for active vitamin D synthesis in its monocyte/macrophage system that is substantially increased in aging and long-term diabetes mellitus. These conditions are also characterized by significant increases in vitamin D receptor expression in hepatocytes. The present study suggests that VDR signaling system could be a potential target in prevention of liver complications caused by diabetes and aging.