Associations of maternal urinary rare earth elements individually and in mixtures with neonatal size at birth.

Prenatal rare earth elements (REEs) exposure is linked to unfavorable health consequences. Epidemiologic research on repeated measurements of REEs during gestation correlated with fetal growth is exiguous. Until now, few studies have characterized exposure characteristics of REEs in pregnant women. We aimed to ascertain the characteristics and predictors of REEs exposure over three trimesters among pregnant women and examine the possible effects of prenatal REEs exposure on size at birth. Urinary REEs concentrations exhibited considerable within-subject variation with intraclass correlation coefficients ranging from 0.16 to 0.58. Maternal age, household income, gestational weight gain, passive smoking during pregnancy, parity, and neonatal gender were associated with maternal urinary REEs concentrations. Elevated maternal urinary holmium and thulium concentrations in the 3rd trimester were significantly related to reductions in birth weight. Weighted quantile sum (WQS) regression model identified that urinary REEs mixture in the 3rd trimester were negatively related to birth weight (WQSREEs ß = -26.22; 95% confidence interval [CI]: -47.62, -4.82), with holmium (40%) and thulium (24%) receiving the highest weights. Male infants received the most weight (>50%) related to decreased birth weight. This study revealed a significant association between individual and mixture REE exposure in late pregnancy with a reduction in birth weight.

Holmium (III)-doped multifunctional nanotheranostic agent for ultra-high-field magnetic resonance imaging-guided chemo-photothermal tumor therapy.

Ultra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Despite being the most commonly used MRI contrast agents, gadolinium chelates perform poorly in high magnetic fields, which significantly weakens their T1 intensity. In comparison, the rare element Holmium (Ho)-based nanoparticles (NPs) have demonstrated great potential as T2-weighted MRI contrast agents in UHF MRI due to their extremely short electron relaxation times (∼ 10-13s). In this study, a multifunctional nanotherapeutic probe was designed for UHF MRI-guided chemotherapy and photothermal therapy. The Ho (III)-doped mesoporous polydopamine (Ho-MPDA, HM) nanosphere was loaded with the chemotherapeutic drug mitoxantrone (MTO) and then coated with 4T1 cell membranes to enhance active targeting delivery to breast cancer. The prepared nanotherapeutic probe MTO@HMM@4T1 (HMM@T) exhibited good biocompatibility, high drug-loading capability and great potential as Ho (III)-based UHF MRI contrast agents. Moreover, the biodegradation of HMM@T in response to the intratumor pH and glutathione (GSH) promotes MTO release. Near-infrared (NIR) light irradiation of HM induced photothermal therapy and further enhanced drug release. Consequently, HMM@T effectively acted as an MRI-guided tumor-targeting chemo-photothermal therapy against 4T1 breast cancer. STATEMENT OF SIGNIFICANCE: Ultra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Although gadolinium chelates are the most commonly used MRI contrast agents in clinical practice, they exhibit a significantly decreased T1 relaxivity at UHF. Holmium exhibits outstanding UHF magnetic resonance capabilities in comparison with gadolinium chelates currently used in clinic. Herein, a theranostic nanodrug (HMM@T) was designed for UHF MRI-guided chemo-photothermal therapy. The nanodrug possessed remarkable UHF T2 MRI properties (r2 = 152.13 mM-1s-1) and high drug loading capability of 18.4 %. The biodegradation of HMM@T NPs under triple stimulations of pH, GSH, and NIR led to an efficient release of MTO in tumor microenvironment. Our results revealed the potential of a novel UHF MRI-guided multifunctional nanosystem in cancer treatment.

Dysprosium and Holmium Vanadate Nanoprobes as High-Performance Contrast Agents for High-Field Magnetic Resonance and Computed Tomography Imaging.

We describe a wet chemical method for the synthesis of uniform and well-dispersed dysprosium vanadate (DyVO4) and holmium vanadate (HoVO4) nanoparticles with an almost spherical shape and a mean size of ∼60 nm and their functionalization with poly(acrylic acid). The transverse magnetic relaxivity of both systems at 9.4 T is analyzed on the basis of magnetic susceptibility and magnetization measurements in order to evaluate their potential for application as high-field MRI contrast agents. In addition, the X-ray attenuation properties of these systems are also studied to determine their capabilities as computed tomography contrast agent. Finally, the colloidal stability under physiological pH conditions and the cytotoxicity of the functionalized NPs are also addressed to assess their suitability for bioimaging applications.

Safety analysis of holmium-166 microsphere scout dose imaging during radioembolisation work-up: A cohort study.

OBJECTIVE: Radioembolisation is generally preceded by a scout dose of technetium-99m-macroaggregated albumin to estimate extrahepatic shunting of activity. Holmium-166 microspheres can be used as a scout dose (±250 MBq) and as a therapeutic dose. The general toxicity of a holmium-166 scout dose (166Ho-SD) and safety concerns of an accidental extrahepatic deposition of 166Ho-SD were investigated. METHODS: All patients who received a 166Ho-SD in our institute were reviewed for general toxicity and extrahepatic depositions. The absorbed dose in extrahepatic tissue was calculated on SPECT/CT and correlated to clinical toxicities. RESULTS: In total, 82 patients were included. No relevant clinical toxicity occurred. Six patients had an extrahepatic deposition of 166Ho-SD (median administered activity 270 MBq). The extrahepatic depositions (median activity 3.7 MBq) were located in the duodenum (3x), gastric fundus, falciform ligament and the lesser curvature of the stomach, and were deposited in a median volume of 15.3 ml, which resulted in an estimated median absorbed dose of 3.6 Gy (range 0.3-13.8 Gy). No adverse events related to the extrahepatic deposition of the 166Ho-SD occurred after a median follow-up of 4 months (range 1-12 months). CONCLUSION: These results support the safety of 250 MBq 166Ho-SD in a clinical setting. KEY POINTS: • A holmium-166 scout dose is safe in a clinical setting. • Holmium-166 scout dose is a safe alternative for 99m Tc-MAA for radioembolisation work-up. • Holmium-166 scout dose potentially has several benefits over 99m Tc-MAA for radioembolisation work-up.

Preparation and complex characterization of silica holmium sol-gel monoliths.

Amorphous, sol-gel derived SiO(2) are known to biocompatible and bioresorbable materials. Biodegradable and inert materials containing radioactive isotopes have potential application as delivery vehicles of the beta radiation to the cancer tumors inside the body. Incorporation of holmium in the sol-gel derived SiO(2) could lead to the formation of a biodegradable material which could be used as carrier biomaterial for the radiation of radioactive holmium to the various cancer sites. The homogeneity of the prepared sol-gel silica holmium monoliths was investigated by Back Scattered Electron Imaging of Scanning Electron Microscope equipped with Energy Dispersive X-ray Analysis, X-ray Induced Photoelectron Spectroscopy and Nuclear Magnetic Resonance Spectroscopy. The biodegradation of the monoliths was investigated in Simulated Body Fluid and TRIS (Trizma pre-set Crystals) solution. The results show that by suitable tailoring of the sol-gel processing parameters holmium can be homogeneously incorporated in the silica matrix with a controlled biodegradation rate.

Microcalorimetric studies of the biological effects of Ho(III) on Halobacterium halobium R1.

The biological effect of Ho3+ on Halobacterium halobium R1 growth was analyzed using the microcalorimetric method. Using the LKB-2277 Bioactivity Monitor with the ampoule method at 37 degrees C, the thermogenic curves of the growth of H. halobium R1 were obtained. Then, the maximum power (P (m)) and the growth rate constants (k) were determined, and the values of P (m) and k were linked to the concentration of Ho3+. In all, the addition of Ho3+ cause a decrease in the maximum heat production and growth rate constants. To confirm the results, the shapes of H. halobium R1 cell addition with Ho3+ using a transmission electron microscope (TEM) were observed. According to the thermogenic curves and TEM photos of H. halobium R1 under different conditions, it is clear that the metabolic mechanism of H. halobium R1 growth has been changed with the addition of Ho3+.

Microcalorimetric studies of the biological effect of holmium (III) on Halobacterium halobium R1 growth.

The biological effect of Ho3+ on Halobacterium halobium R1 growth was analyzed by a microcalorimetric technique. By means of LKB-2277 Bioactivity Monitor, ampoule method at 37 degrees C, we obtained the thermogenic curves of H. halobium R1 growth. To analyze the results, the maximum power (Pm) and the growth rate constants (k) were determined, which show that values of Pm and k are linked to the concentration of Ho3+. In all, the addition of Ho3+ causes a decrease of the maximum heat production and growth rate constants. For comparison, we observed the shapes of H. halobium R1 cell by means of transmission electron microscope (TEM). According to the thermogenic curves and TEM photos of H. halobium R1 under different conditions, it is clear that metabolic mechanism of H. halobium R1 growth has been changed with the addition of Ho3+.

Brachytherapy: state of the art and possible improvements.

Cancer often remains an incurable disease, despite significant progresses in diagnosis and treatment that have been made. Specifically, the use of nuclear medicine in oncology is greatly contributing to both imaging and therapy aspects. Targeted therapies are a major field of interest since it increases efficiency and reduces side effects. Brachytherapy is among the most valuable of recent developments for treating localized tumours resulting in improvements in improved quality of life. This is primarily because it irradiates cancerous cells most exclusively while barely effecting healthy tissue. The use of radiochemicals implies specific management for production, transport and handling that have limited the development of this technique. This review article describes brachytherapy and their latest developments. Furthermore, alternative activation methods for the production of radioisotopes and a novel delivery system for targeted multi-therapy by using PLA-ferrite nanospheres are described.

Hybrid scatter correction applied to quantitative holmium-166 SPECT.

Ho-166 is a combined beta-gamma emitter of which the betas can be used therapeutically. From the 81 keV gammas of Ho-166, SPECT images can be obtained, which give opportunities to guide Ho-166 therapy. Accurate reconstruction of Ho-166 images is currently hampered by photopeak-scatter in the patient, down-scatter in the detector, collimator and patient caused by the 1.4 MeV photons and by bremsstrahlung. We developed and validated a method for quantitative SPECT of Ho-166 that involves correction for both types of scatter plus non-uniform attenuation correction using attenuation maps. Photopeak-scatter (S) is compensated for by a rapid 3D Monte Carlo (MC) method that is incorporated in ordered subset (OS) reconstruction of the emission data, together with simultaneous correction for attenuation (A) and detector response (D); this method is referred to as OS-ADS. Additionally, for correction of down-scatter, we use a 14 keV wide energy window centred at 118 keV (OS-ADSS). Due to a limited number of available energy windows, the same 118 keV energy window was used for down-scatter correction of the simultaneously acquired Gd-153 transmission data. Validations were performed using physical phantom experiments carried out on a dual-head SPECT system; Gd-153 transmission line sources were used for acquiring attenuation maps. For quantitative comparison of OS-ADS and OS-ADSS, bottles filled with Ho-166 were placed in both a cylindrical phantom and an anthropomorphic thorax phantom. Both OS-ADS and OS-ADSS were compared with an ordered subset reconstruction without any scatter correction (OS-AD). Underestimations of about 20% in the attenuation map were reduced to a few per cent after down-scatter correction. The average deviation from the true activity contained in the bottles was +72% with OS-AD. Using OS-ADS, this average overestimation was reduced to +28% and with OS-ADSS the deviation was further reduced to 16%. With OS-AD and OS-ADS, these numbers were more sensitive to the choice of volumes of interest than with OS-ADSS. For the reconstructed activity distributions, erroneous background activity found with OS-AD was reduced by a factor of approximately 2 by applying OS-ADS and reduced by a factor of approximately 4 by applying OS-ADSS. The combined attenuation, photopeak-scatter and down-scatter correction framework proposed here greatly enhanced the quantitative accuracy of Ho-166 imaging, which is of the uppermost importance for image-guided therapies. It is expected that the method, with adapted window settings, also can be applied to other isotopes with high energy peaks that contaminate the photopeak data, such as I-131 or In-111.

Therapeutic effects of Holmium-166 chitosan complex in rat brain tumor model.

This study examined the effectiveness of Holmium-166 (Ho-166) chitosan complex therapy for a malignant glioma. Cultured C6 glioma cells (100,000 in 5 microl) were injected into the caudate/putamen of 200-250 gram Wistar rats. Five days later, a Ho-166 chitosan complex was injected into the same site of the glioma injection. Four injection doses were administered: the control group received PBS 10 microl, group 1 received an injection of 100 microCi (10 microl), group 2 received an injection of 50 microCi (5 microl), and group 3 received an injection of 10 microCi (1 microl). The average tumor volume for each group was 1.385 mm3 for the control group, 0.036 mm3 for group 1, 0.104 mm3 for group 2, and 0.111 mm3 for group 3. Compared with the control group, the size of the tumors in groups 1, 2 and 3 was reduced by an average of 97.4%, 92.5% and 91.9%, respectively. The Kaplan-Meier survival curve of group 2 was the longest, followed by groups 3, group 1 and the control. The mean survival was 22.8, 59, 60, and 44.6 days for the control group and groups 3, 2 and 1, respectively. H-E staining revealed that group 2 yielded the best results in the destruction of the malignant glioma. TUNEL staining and immunohistochemical studies indicated apoptotic features. The Ho-166 chitosan complex proved to be effective in destroying the malignant glioma.

Therapeutic Effects of Holmium-166 Chitosan Complex in Rat Brain Tumor Model

This study examined the effectiveness of Holmium-166 (Ho-166) chitosan complex therapy for a malignant glioma. Cultured C6 glioma cells (100, 000 in 5microliter) were injected into the caudate/putamen of 200 - 250 gram Wistar rats. Five days later, a Ho-166 chitosan complex was injected into the same site of the glioma injection. Four injection doses were administered: the control group received PBS 10microliter, group 1 received an injection of 100micro Ci (10microliter), group 2 received an injection of 50microCi (5microliter), and group 3 received an injection of 10micro Ci (1microliter). The average tumor volume for each group was 1.385 mm3 for the control group, 0.036 mm3 for group 1, 0.104 mm3 for group 2, and 0.111 mm3 for group 3. Compared with the control group, the size of the tumors in groups 1, 2 and 3 was reduced by an average of 97.4%, 92.5% and 91.9%, respectively. The Kaplan-Meier survival curve of group 2 was the longest, followed by groups 3, group 1 and the control. The mean survival was 22.8, 59, 60, and 44.6 days for the control group and groups 3, 2 and 1, respectively. H-E staining revealed that group 2 yielded the best results in the destruction of the malignant glioma. TUNEL staining and immunohistochemical studies indicated apoptotic features. The Ho-166 chitosan complex proved to be effective in destroying the malignant glioma.

Radiation synovectomy with holmium-166 ferric hydroxide macroaggregate in equine metacarpophalangeal and metatarsophalangeal joints.

OBJECTIVES: To evaluate the effects of radiation synovectomy (RSYN) with holmium-166 ferric hydroxide macroaggregate (Ho-166 FHMA) on synovium and synovial fluid in normal metacarpo- and metatarsophalangeal joints of horses and to determine intraarticular distribution of radioactivity after Ho-166 FHMA treatment. STUDY DESIGN: Either Ho-166 FHMA or nonradioactive Ho-165 FHMA was injected into metacarpo- or metatarsophalangeal joints. ANIMALS: Six adult mixed-breed horses without any clinical evidence of metacarpo- or metatarsophalangeal joint disease. METHODS: Joints were injected with a single high dose of Ho-166 FHMA (mean, 1,000 MBq/joint) or a nonradioactive Ho-165 FHMA preparation (controls). Clinical examination, arthroscopy, synovial fluid analyses, and histologic studies were performed to detect effects of RSYN. Scintigraphy was used to localize intraarticular distribution of Ho-166 FHMA. RESULTS: Ho-166 FHMA treatment induced joint inflammation leading to regional edema, effusion, and scar tissue formation. Scintigraphy revealed the highest intensity of radioactivity in the proximal plantar joint pouch, at which the Ho-166 FHMA treatment caused multifocal necrosis. In the dorsal joint pouch, however, arthroscopic study and histologic analysis showed very little effect of RSYN. There was no regeneration of synovium evident within 2 months. Synovial fluid protein concentration was significantly (P <.01) elevated, and some residual radioactivity remained for 5 days after Ho-166 FHMA injection. CONCLUSIONS: Injection of a single high dose of Ho-166 FHMA caused multifocal necrosis of synovium and deep, soft-tissue injury in equine fetlock joints. CLINICAL RELEVANCE: Inflamed equine joints with synovial lining hyperplasia could benefit from Ho-166 FHMA-induced radiation synovectomy if excessive scar tissue formation can be avoided.

Inhibition of transiently expressed low- and high-voltage-activated calcium channels by trivalent metal cations.

Calcium channels are important regulators of neuronal excitability and contribute to transmitter release, calcium dependent gene expression, and oscillatory behavior in many cell types. Under physiological conditions, native low-voltage (T-type)- and high-voltage-activated (HVA) currents are potently inhibited by trivalent cations. However, the presence of multiple calcium channel isoforms has hampered our ability to unequivocally assess the effects of trivalent cations on channel activity. Here, we describe the actions of nine trivalent metal ions on transiently expressed alpha1G (Cav3.1) T-type calcium channels cloned from human brain. In 2 mM external barium solution, yttrium most potently inhibited alpha1G current (IC50 = 28 nM), followed by erbium > gadolinium ~ cerium > holmium > ytterbium > neodymium > lanthanum >> scandium. With the exception of scandium, blocking affinity was loosely correlated with decreasing ionic radius. A detailed characterization of yttrium block revealed a 25-fold decrease in blocking affinity when the external concentration of charge carrier was increased from 2 mM to 20 mM. In 20 mM barium, yttrium also effectively inhibited various types of cloned HVA channels indicating that this ion is a nonselective blocker. For all calcium channels examined, yttrium preferentially inhibited inward over outward current, but block was otherwise voltage independent. In addition to peak current inhibition, P/Q- and L-type channels underwent a unique speeding of the macroscopic time course of inactivation. Whereas peak current block of alpha1A channels was highly sensitive to the external charge carrier concentration, the inactivation effects mediated by yttrium were not, suggesting that the two effects are due to distinct mechanisms. Moreover, the speeding effect was greatly attenuated by manipulations that slowed the inactivation kinetics of the channels. Thus, our evidence suggests that yttrium effects are mediated by two distinct events: peak current block likely occurring by occlusion of the pore, and kinetic speeding arising from yttrium interactions with the channel that alter the state of the inactivation gate.

Choanal atresia in premature dizygotic twins--a transnasal approach with Holmium:YAG-laser.

Twins born prematurely presented with choanal atresia and were successfully treated using a transnasal, endoscopically and microscopically controlled Ho:YAG-Laser assisted technique. One twin, who had bilateral choanal atresia was operated immediately, the other one, with unilateral choanal atresia, received surgery 8 months after birth. The rare feature of twins both suffering from choanal atresia and a technique for definitive treatment of this disease in premature neonates are presented and discussed. This report of dizygotic twins with nonsyndromal choanal atresia suggests the possibility of an autosomal recessive inheritance with various penetration or an undefined teratogenic etiologic factor.

Determination of the position of the Qi.- quinone binding site from the protein surface of the cytochrome bc1 complex in Rhodobacter capsulates chromatophores.

The technique of distance measurement, utilizing spin relaxation enhancement by an external probe, has been extended to the study of intrinsic semiquinone radicals through the use of holmium-EDTA complexes and continuous wave electron paramagnetic resonance spectroscopy. This technique has been used to determine the distance of the semiquinone anion, Qi (also designated as Qn.- or Qc.-), from the surface of the ubiquinone cytochrome c oxidoreductase, consisting of only three subunits, in membrane particles from Rhodobacter capsulates. The location of the semiquinone anion is 6-10 A from the N side protein, establishing that there are two separate quinone reaction sites, i.e., 'Qi' and 'Qo', within this complex on opposite sides of the membrane. The results are discussed in relation to reported ENDOR, EPR, and optical studies of the mitochondrial counterpart.

Inhibition of phagocytosis of polymorphonuclear leucocytes by adenosine and HoCl3 in vitro.

Phagocytosis of polymorphonuclear leucocytes treated with NaF, HoCl3 and adenosine were studied. The highest concentration used was 25 mM of NaF, 25 mM of adenosine and 5 mM of HoCl3. It was ascertained that these substances, inhibitors of erythrocyte contractile protein, inhibit both phagocytosis and ability of polymorphonuclear leucocytes to change their shape. These unfavourable effects may be induced by the chemicals interfering with polymorphonuclear leucocytes contractile protein. NaF, HoCl3 and adenosine are also responsible for morphological changes in the cell nucleus.

Binding of fluorescent lanthanides to rat liver mitochondrial membranes and calcium ion-binding proteins.

(1) Tb3+ binding to mitochondrial membranes can be monitored by enhanced ion fluorescence at 545 nm with excitation at 285 nm. At low protein concentrations (less than 30 mug/ml) no inner filter effects are observed. (2) This binding is localized at the external surface of the inner membrane and is unaffected by inhibitors of respiration or oxidative phosphorylation. (3) A soluble Ca2+ binding protein isolated according to Lehninger, A.L. ((1971) Biochem. Biophys. Res. Commun. 42, 312-317) also binds Tb3+ with enhanced ion fluorescence upon excitation at 285 nm. The excitation spectrum of the isolated protein and of the intact mitochondria are indicative of an aromatic amino acid at the cation binding site. (4) Further characterization of the Tb3+-protein interaction revealed that there is more than one binding site per protein molecule and that these sites are clustered (less than 20 A). Neuraminidase treatment or organic solvent extraction of the protein did not affect fluorescent Tb3+ binding. (5) pH dependency studies of Tb3+ binding to the isolated protein or intact mitochondria demonstrated the importance of an ionizable group of pK greater than 6. At pH less than 7.5 the amount of Tb3+ bound to the isolated protein decreased with increase in pH as monitored by Tb3+ fluorescence. With intact mitochondria the opposite occurred with a large increase in Tb3+ fluorescence at higher pH. This increase was not observed when the mitochondria were preincubated with antimycin A and rotenone.