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Objectives The purpose of this study was to compare Gd levels in rat tissues after cumulative exposure to four commercially available macrocyclic gadolinium-based contrast agents (GBCAs). Methods Sixty-five male Sprague-Dawley rats were randomized to four exposure groups ( n  = 15 per group) and one control group ( n  = 5). Animals in each exposure group received 20 GBCA administrations (four per week of ProHance®, Dotarem®, Clariscan™, or Gadovist® for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After 28-days’ recovery, animals were sacrificed and tissues harvested for Gd determination by inductively coupled plasma-mass spectroscopy (ICP-MS). Histologic assessment of the kidney tissue was performed for all animals. Results Significantly ( p  ≤ 0.005; all evaluations) lower Gd levels were noted with ProHance® than with Dotarem®, Clariscan™, or Gadovist® in all soft tissue organs: 0.144 ± 0.015 nmol/g vs. 0.342 ± 0.045, 0.377 ± 0.042, and 0.292 ± 0.047 nmol/g, respectively, for cerebrum; 0.151 ± 0.039 nmol/g vs. 0.315 ± 0.04, 0.345 ± 0.053, and 0.316 ± 0.040 nmol/g, respectively, for cerebellum; 0.361 ± 0.106 nmol/g vs. 0.685 ± 0.330, 0.823 ± 0.495, and 1.224 ± 0.664 nmol/g, respectively, for liver; 38.6 ± 25.0 nmol/g vs. 172 ± 134, 212 ± 121, and 294 ± 127 nmol/g, respectively, for kidney; and 0.400 ± 0.112 nmol/g vs. 0.660 ± 0.202, 0.688 ± 0.215, and 0.999 ± 0.442 nmol/g, respectively, for skin. No GBCA-induced macroscopic or microscopic findings were noted in the kidneys. Conclusions Less Gd is retained in the brain and body tissues of rats 28 days after the last exposure to ProHance® compared to other macrocyclic GBCAs, likely due to unique physico-chemical features that facilitate more rapid and efficient clearance.

Background Gd levels are higher in tissues of animals with compromised renal function, but studies to compare levels after exposure to different macrocyclic gadolinium-based contrast agents (GBCAs) are lacking. We compared Gd levels in tissues of subtotally nephrectomised (SN) rats after repeated exposure to macrocyclic GBCAs. Methods Sprague–Dawley SN male rats (19 per group) received 16 injections of gadoteridol, gadobutrol, or gadoterate meglumine at 0.6 mmol Gd/kg 4 times/weeks over 4 weeks. A control group of healthy male rats ( n  = 10) received gadoteridol at the same dosage. Plasma urea and creatinine levels were monitored. Blood, cerebrum, cerebellum, liver, femur, kidney(s), skin and peripheral nerves were harvested for Gd determination by inductively coupled plasma-mass spectrometry at 28 and 56 days after the end of treatment. Results Plasma urea and creatinine levels were roughly twofold higher in SN rats than in healthy rats at all timepoints. At day 28, Gd levels in the peripheral nerves of gadobutrol- or gadoterate-treated SN animals were 5.4 or 7.2 times higher than in gadoteridol-treated animals ( p  < 0.001). Higher Gd levels after administration of gadobutrol or gadoterate versus gadoteridol were also determined in kidneys ( p  ≤ 0.002), cerebrum ( p  ≤ 0.001), cerebellum ( p  ≤ 0.003), skin ( p  ≥ 0.244), liver ( p  ≥ 0.053), and femur ( p  ≥ 0.271). At day 56, lower Gd levels were determined both in SN and healthy rats for all GBCAs and tissues, except the femur. Conclusions Gd tissue levels were lower following gadoteridol exposure than following gadobutrol or gadoterate exposure.

The adhesion molecule P-selectin is present on the cell surface of both activated endothelium and activated platelets. The present study describes the pharmaceutical development, safety evaluation, and preclinical efficacy of a micro-dosed radiotracer. The macromolecular nanoscale assembly consisted of a natural compound made of a sulfated fucose-rich polysaccharides (fucoidan) and a radionuclide (technetium-99m) for the detection of P-selectin expression in cardiovascular diseases. After extraction and fractionation from brown seaweeds, the good manufacturing practice (GMP) production of a low molecular weight (LMW) fucoidan of 7 kDa was achieved and full physicochemical characterization was performed. The regulatory toxicology study in rats of the GMP batch of LMW fucoidan revealed no adverse effects up to 400 μg/kg (×500 higher than the expected human dose) and pseudoallergy was not seen as well. In a myocardial ischemia-reperfusion model in rats, the GMP-grade LMW fucoidan labeled with technetium-99m detected P-selectin upregulation in vivo. The present study supports the potential of using 99mTc-fucoidan as an imaging agent to detect activated endothelium in humans.

Sulfate conjugation of thyroid hormones is an alternate metabolic pathway that facilitates the biliary and urinary excretion of iodothyronines and enhances their deiodination rate, leading to the generation of inactive metabolites. A desulfating pathway reverses this process, and thyromimetic effects have been observed following the parenteral administration of 3,5,3'-triiodothyronine (T3) sulfate (T3S) in rats. The present study investigated whether T3S is absorbed after oral administration in humans and if it represents a source of T3. Twenty-eight hypothyroid patients (7 men and 21 women; mean age, 44 ± 11 years) who had a thyroidectomy for thyroid carcinoma were enrolled. Replacement thyroid hormone therapy was withdrawn (42 days for thyroxine, 14 days for T3) prior to 131I remnant ablation. A single oral dose of 20, 40, 80 (4 patients/group), or 160 μg (16 patients/group) of T3S was administered 3 days before the planned administration of 131I. Blood samples for serum T3S and total T3 (TT3) concentrations were obtained at various times up to 48 hours after T3S administration. At all T3S doses, serum T3S concentrations increased, reaching a peak at 2 to 4 hours and progressively returning to basal levels within 8 to 24 hours. The T3S maximum concentration (Cmax) and area under the 0- to 48-hour concentration-time curve (AUC0-48h) were directly and significantly related to the administered dose. An increase in serum TT3 concentration was observed (significant after 1 hour), and the concentration increased further at 2 and 4 hours and then remained steady up to 48 hours after T3S administration. There was a significant direct correlation between the TT3 AUC0-48h and the administered dose of T3S. No changes in serum free thyroxine (T4) concentrations during the entire study period were observed, whereas serum thyroid-stimulating hormone levels increased slightly at 48 hours, but this was not related to the dose of T3S. No adverse events were reported. (1) T3S is absorbed following oral administration in hypothyroid humans; (2) after a single oral dose, T3S is converted to T3 in a dose-dependent manner, resulting in steady-state serum T3 concentrations for 48 hours; (3) T3S may represent a new agent in combination with T4 in the therapy of hypothyroidism, if similar conversion of T3S to T3 can be demonstrated in euthyroid patients who are already taking T4.

The adhesion molecule P-selectin is present on the cell surface of both activated endothelium and activated platelets. The present study describes the pharmaceutical development, safety evaluation, and preclinical efficacy of a micro-dosed radiotracer. The macromolecular nanoscale assembly consisted of a natural compound made of a sulfated fucose-rich polysaccharides (fucoidan) and a radionuclide (technetium-99m) for the detection of P-selectin expression in cardiovascular diseases. After extraction and fractionation from brown seaweeds, the good manufacturing practice (GMP) production of a low molecular weight (LMW) fucoidan of 7 kDa was achieved and full physicochemical characterization was performed. The regulatory toxicology study in rats of the GMP batch of LMW fucoidan revealed no adverse effects up to 400 μg/kg (×500 higher than the expected human dose) and pseudoallergy was not seen as well. In a myocardial ischemia-reperfusion model in rats, the GMP-grade LMW fucoidan labeled with technetium-99m detected P-selectin upregulation in vivo. The present study supports the potential of using 99mTc-fucoidan as an imaging agent to detect activated endothelium in humans.

Sulfate conjugation of thyroid hormones is an alternate metabolic pathway that facilitates the biliary and urinary excretion of iodothyronines and enhances their deiodination rate, leading to the generation of inactive metabolites. A desulfating pathway reverses this process, and thyromimetic effects have been observed following the parenteral administration of 3,5,3'-triiodothyronine (T^sub 3^) sulfate (T^sub 3^S) in rats. The present study investigated whether T^sub 3^S is absorbed after oral administration in humans and if it represents a source of T^sub 3^. At all T^sub 3^S doses, serum T^sub 3^S concentrations increased, reaching a peak at 2 to 4 hours and progressively returning to basal levels within 8 to 24 hours. The T^sub 3^S maximum concentration and area under the 0- to 48-hour concentration-time curve were directly and significantly related to the administered dose. An increase in serum total T^sub 3^ concentration was observed, and the concentration increased further at 2 and 4 hours and then remained steady up to 48 hours after T^sub 3^S administration.

The countries of Kazakhstan, Kyrgyz Republic, Tajikistan, Turkmenistan, and Uzbekistan in Central Asia are highly prone to natural hazards, particularly floods, earthquakes, and landslides. The European Union, in collaboration with the World Bank and the Global Facility for Disaster Reduction and Recovery (GFDRR), created the programme Strengthening Financial Resilience and Accelerating Risk Reduction in Central Asia (SFRARR) to advance disaster and climate resilience in the region. As part of the SFRARR project, the “Regionally consistent risk assessment for earthquakes and floods and selective landslide scenario analysis for strengthening financial resilience and accelerating risk reduction in Central Asia” was developed to achieve the project's objectives. This article presents the data, model, methodology, and results for the five Central Asian countries of the flood risk assessment, which represents the first high-resolution regional-scale transboundary risk assessment study in the area aiming to provide tools for decision-making. The output information will inform and enable the World Bank to initiate a policy dialogue. A fully probabilistic risk assessment for fluvial floods has been carried out for these countries to support regional and national risk financing and insurance applications, including potential indemnity and/or parametric risk financing solutions for a regional programme. A homogenised risk assessment methodology for the five countries and across multiple hazards (floods and earthquakes) and asset types has been adopted to obtain strategic financial solutions consistent across geographical areas and economic sectors. The largest relative (to the total exposed value) expected annual damages are found in Kazakhstan and Tajikistan, with values above 6 ‰. In the five considered countries, the largest relative expected annual damages by sector are found for the transport and agricultural sectors. Climate change is expected to have contrasting impacts, with increases in risk for some regions (the most severe increase is found in the Mangistauskaya region in Kazakhstan) and decreases for other regions (Lebap, Turkmenistan; Khatlon, Tajikistan; Samarkand, Uzbekistan; and Batken, Kyrgyz Republic).

Postacute sequelae of SARS-CoV-2 infection (PASC), including persistent symptoms and acute and chronic diagnoses, have become a major research focus. Diabetes mellitus, beyond its established link to COVID-19 severity, is increasingly recognized as a potential long-term outcome. This study investigated the association between SARS-CoV-2 infection and incident diabetes using population-level health administrative data (HAD) from the Agency for Health Protection of Milan, where the epicenter of the pandemic in Italy took place. This retrospective cohort study included adult residents without a history of diabetes who underwent SARS-CoV-2 testing between 1 March and 31 December 2020. Test-positive individuals were matched 1:1 to test-negative individuals based on sex, age, and testing week. The cohort was followed through 31 December 2021. The incidence of diabetes, identified using an HAD-based case-detection algorithm, was compared between the two groups, and in stratified analyses by sex and age, using weighted Cox models adjusted for chronic comorbidities, area-level deprivation, influenza and pneumococcal vaccinations. Weights were calculated via the inverse probability weighting approach. Effect estimates are presented as hazard ratios (HRs). Our final cohort included 248,176 residents (124,026 test-negative, 124,150 test-positive). Over a median follow-up time of 415 days, 739 positive (0.60%) and 657 negative (0.53%) individuals were newly identified with diabetes. The incidence among positive individuals was 572.82 per 100,000 person-years (CI 531.52-614.12), and that among negative individuals was 509.50 per 100,000 person-years (CI 470.54-548.46). The overall HR was 1.13 (CI 1.02-1.25). In stratified analyses, this effect was prominent in women aged 41-60 years (HR 1.31; CI 1.02-1.68). This study provides population-based evidence supporting an association between SARS-CoV-2 infection and newly detected diabetes. These findings contribute to understanding the long-term health impact of COVID-19 and may inform public health strategies for PASC prevention and management.

Aim of this work was to assess the role of polymorphisms belonging to genes involved in the regulation of ionic homeostasis in Caucasian patients with Ménière Disease (MD). We recruited 155 patients with definite Ménière Disease and 186 controls (Control Group 1) without a lifetime history of vertigo, overlapping with patients for age and rate of hypertension. We validated the positive results on 413 Caucasian subjects selected from a European general population (Control Group 2). The clinical history for migraine and hypertension was collected; genomic DNA was characterized for a panel of 33 SNPs encoding proteins involved in ionic transport. We found a higher rate of migraineurs in MD subjects compared to Group 1 (46.8 vs 15.5%, p  = 0.00005). Four SNPs displayed differences in MD patients compared to Group 1 controls: rs3746951 and rs2838301 in SIK1 gene, rs434082 and rs487119 in SLC8A1; the p values of Chi-squared test for genotype frequencies are 0.009, 0.023, 0.009 and 0.048, respectively. SLC8A1 gene encodes for Na + -Ca ++ exchanger, while SIK1 gene encodes for Salt Inducible Kinase 1, an enzyme associated with Na + -K + ATPase function. The validation with Control Group 2 displayed that only rs3746951 and rs487119 are strongly associated to MD ( p  = 0.001 and p  = 0.0004, respectively). These data support the hypothesis that a genetically induced dysfunction of ionic transport may act as a predisposing factors to develop MD.