Necrotizing sarcoid granulomatosis in a family of patients with sarcoidosis reinforces the association between both entities

Necrotizing sarcoid granulomatosis (NSG) is a rare entity mainly characterized by a prominent granulomatous vasculitis affecting middle-aged or old individuals and with a favorable prognosis. Although many believe it is a variant of sarcoidosis, the proper classification is still a matter of debate as some of its features are found in sarcoidosis but also in Churg-Strauss syndrome, Wegener's disease and hypersensitivity pneumonitis. In this paper, we described for the first time a case of NSG in a family with several cases of sarcoidosis, reinforcing the relationship between NSG and sarcoidosis. Additional interesting findings were the young age of the patient (15 years old), the symptoms limited to the respiratory tract (uncommon when NSG affects youngsters) and the increase in serologic markers of autoimmune disease. Though complete criteria for autoimmune disease were not present, systemic lupus erythematosus and Sjogren's syndrome are possible candidates. As sarcoidosis is described to be associated with several autoimmune diseases, this finding is an additional suggestion of the relationship between both entities.     

The effects of resistance training in patients with primary Sjogren’s syndrome

Clinical Rheumatology - Resistance training (RT) is well tolerated and has shown promise for decreasing fatigue. However, the effects of RT have never been examined in primary Sjogren’s...     

Peroxoniobium inhibits leukemia cell growth

A new class of polyoxoniobate complex has been synthesized and characterized as a novel anticancer agent for photodynamic therapy. The complex inhibits the growth of chronic myelogenous leukemia cells with an IC₅₀ value of 30 μM, in the dark. However, upon exposure to light (365 nm) there is a fivefold increase in the cytotoxic activity. Light radiation activate the complex with the formation of radical species capable of interacting with DNA according to our experimental and theoretical data.

A new class of polyoxoniobate complex has been synthesized and characterized as a novel anticancer agent for photodynamic therapy.

In this work, we prepared a photosensitive peroxoniobium complex presenting a balance with an active radical phase when illuminated with radiation of 365 nm. A versatile niobium species of amorphous structure was obtained by the reaction of niobium ammonium oxalate with ammonium hydroxide up to pH 7. The material obtained, a niobium oxyhydroxide (NbO₂(OH)) (white solid),^1,2 can be modified with the generation of NbO₂(OH)O₂˙⁻ peroxo groups (yellow solid).³ The yellow compound is formed by treatment with H₂O₂. The absorption radiation in the visible region due to the charge transfer transition between the peroxo group and the niobium is shown in Fig. 1.Open in a separate windowFig. 1UV-Vis profile of the catalysts.This complex with the radical as an intermediate is favored in the presence of visible and UV radiation. This property is of interest for photodynamic therapy of cancer (PDT), which involves the exposure of malignant cells containing a photosensitizer molecule to light irradiation, in the presence of oxygen species. The photoactivated drug produces reactive oxygen species that initiate a series of events, resulting in cell death. Selective light activation allows a preferential tumor destruction in comparison to healthy tissues.⁴ Several metal complexes exhibit photocytotoxicity under UV or visible light,^5,6 but data about niobium compounds are very scarce in the literature.⁷The polyoxoniobate, generated from niobium oxyhydroxide described here can be very active in the treatment of diseased cells when illuminated with visible or UV radiation due to its light absorption capacity because of the peroxo groups formed. The peroxoniobium complex has some advantages, such as ease synthesis and in mild conditions, high solubility, low activity under light off, and resistance to inactivation by thiol reagents. Moreover, it is nontoxic⁸ and does not employ noble metals like most of the compounds proposed in the literature. Actually, niobium oxide was tested as a bone implant component and showed absence of inflammatory cells or degeneration of the osteoblasts without any sign of damage to the preexisting bone tissue, showing compatibility with the bone tissue.^9–11The innovative part in the process of obtaining the polyoxoniobate complex presented in this work consists in the leaching of the complex when treating the niobium oxyhydroxide with H₂O₂. With the treatment, a yellow solid and a leached yellow liquid is obtained, which is the complex containing peroxoniobium in its structure, sensitive to the UV-Vis radiation generating radical species. This species generated with the leaching at neutral pH presents high negative charge and a kinetic volume of 223 nm. The XRD of the lyophilized polyoxoniobate indicated strong amorphous character. However, the polyoxoniobate is known to form well defined polyoxometalates such as Lindqvist ([Nb₆O₁₉]⁸⁻) and decaniobate ([Nb₁₀O₂₈]⁶⁻). Fig. 2 shows a comparison between the experimental and PBE/LANL2DZ/aug-cc-pVDZ DFT IR spectra. It is clear that the pattern of the decaniobate structure is closer to the experimental spectrum. One should keep in mind that DFT frequencies are normally 10% underestimated with respect to the experimental values. The broader absorption below 600 cm⁻¹ can be attributed to the interaction between different decaniobate structures forming the amorphous solid. The calculated peaks at 710, 760 and 860 cm⁻¹ are related to the experimental peaks of 800, 870 and 910 cm⁻¹ indicating that decaniobate is the local arrangement of the polyoxoniobate complex.Open in a separate windowFig. 2Infrared spectra for experimental procedures, Lindqvist and decaniobate structures (simulated). The line shape chosen was Lorentzian and the half-width is about 20.The generation of reactive oxygen under radiation was confirmed by the reaction of the complex with an organic dye, which was monitored by UV-Vis spectroscopy (Fig. 3). The spectrum of the dye solution shows the characteristic peak of the methylene blue (MB) at 663 nm (black trace). It can be clearly seen that in the presence of the peroxoniobium complex and radiation (365 nm) the signal decreased indicating the reaction of the peroxoniobium complex with the dye (blue trace). In the absence of light, there is no decrease in the signal related to the dye, indicating the need of the radiation to activate the oxidation action of the peroxoniobium complex. The equilibrium in which the radical species forms it is not necessary to use a photosensitizer agent, such as porphyrins.⁴ A further investigation was carried out by ³¹P NMR (Fig. S1^†) using guanosine as model molecule able to react with the peroxoniobium complex. The ³¹P NMR spectrum shown in Fig. S1-a^† corresponds to 5-GMP and revealed that the phosphorus atom in the structure exhibits a chemical shift at δ 5.93. When 5-GMP and the polyoxoniobate are in contact, no significant changes are observed in the ³¹P spectrum, only a small displacement of the phosphorus signal to δ 5.90 (Fig. S1-b^†). However, when the 5-GMP and polyoxoniobate mixture is submitted to radiation (Fig. S1-c^†), an interaction between the compounds occurs, giving rise to a new species that presents a different chemical shift in the P spectrum (δ 5.27).Open in a separate windowFig. 3UV-Vis profile of the reaction of the Nb complex with the organic dye (10 mg L⁻¹).The effect of the peroxoniobium on the growth of K562 cells was evaluated after 4 h of incubation. The compound inhibits K562 cell growth in a concentration-dependent manner, with an IC₅₀ of 30.0 ± 1.5 μmol L⁻¹. Ammonium niobate(v) oxalate was also tested and it has no effect on K562 cells up to 100 μM. The cytotoxic activity of polyoxoniobate increases by 5 times upon 5 min of UV-A light irradiation, with an IC₅₀ value of 6.2 ± 0.4 μmol L⁻¹ (Fig. 4). The higher activity, when exposed to light, associated to the low toxicity of niobium compounds place the peroxoniobium complex as a candidate for photodynamic therapy.Open in a separate windowFig. 4Photocytotoxic effect of the peroxoniobium complex. K562 cells were incubated for 4 h in the presence of different complex concentrations, in the dark (black bars) and after 5 min of UV-A light exposure (red bars). The values are the average of three independent experiments.There are few reports in the literature about the cytotoxic activity of niobium compounds. A peroxo niobium complex with ascorbic acid (K₃[Nb(Asc)(O₂)₃]) is moderately active in HL60 human leukemia cells but not in K562 human myelogenous leukemia cells.¹² A tetrameric Nb28-containing cluster inhibits the growth of the human breast cancer MCF-7 cells line with an IC₅₀ value of 5.21, after 48 h of incubation.¹³Methylene blue (MB) is one of the main photosensitizing agents used in PDT due to its good tissue penetration and low cytotoxicity.¹⁴ It is active in several types of tumors upon irradiation with red laser light.¹⁵ This fact allied to the ability of the peroxoniobium compound to interact with MB (Fig. 3) prompted us to investigate its effect in the MB photocytotoxicity. We have first checked that exposure to UV-A light did not affect the cytotoxicity of MB in K562 cells (

Exercise training improves the IL-10/TNF-α cytokine balance in the gastrocnemius of rats with heart failure

Objective

This study examined the effects of exercise training (ExT) upon concentration of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) in the gastrocnemius of rats with heart failure (HF) induced by left coronary artery ligation.

Relationship of health literacy and adherence to oral anticoagulation therapy in patients with atrial fibrillation: a cross‐sectional study

Journal of Thrombosis and Thrombolysis - Oral anticoagulant therapy (OAT) has increased substantially due to the aging population and prevalence rise of atrial fibrillation (AF). Medication...     

Water-based resistance training program with isolated concentric action improves physical functional capacity and muscular strength in older women

Background

Resistance training has proven to be an excellent method for counteracting aging physical dysfunctions. However, its application in the liquid environment is not yet fully elucidated.

Aim

To investigate the effects of water-based resistance training (WBRT) with the concentric phase performed as fast as possible, compared to conventional resistance training (CRT), on physical functional capacity, muscle strength, and body composition in older women.

Methods

Thirteen healthy older women participated in the WBRT and 11 in the CRT. Estimation statistics focused on the effect size of the experiment/intervention were used. We also analyzed the intervention effect based on the percentage delta between WBRT and CRT.

Results

The WBRT group showed a negative large effect (d?=?? 0.922; p?=?0.0274) for the timed up and go, and a large effect for chair rise in 30″ and the elbow flex test (d?=?1.58; p?=?0.0012; d?=?2.8; p?=?0.01) respectively. Intervention comparisons based on the delta percentage between WBRT and CRT presented an intermediate effect (d?=?0.606; p?=?0.157) for the stair climb, a large effect (d?=?0.988; p?=?0.0282) for the timed up and go, and a large negative effect [d?=?? 1.32 (90.0% CI ? 1.92, ? 0.646); p?=?0.0038] for the elbow flex test. Concentric extensor-flexor peak torque (60°/s) showed an intermediate effect (d?=?0.749; p?=?0.0876; d?=?0.65; p?=?0.122 respectively). Body fat (%) demonstrated an intermediate effect (d?=?0.523; p?=?0.234).

Conclusion

WBRT with the concentric phase performed as fast as possible was able to improve physical functional capacity and maximal knee extension strength of older women.

     

Time-dependent modulation of AMPA receptor phosphorylation and mRNA expression of NMDA receptors and glial glutamate transporters in the rat hippocampus and cerebral cortex in a pilocarpine model of epilepsy

The pilocarpine model in rodents reproduces the main features of mesial temporal lobe epilepsy related to hippocampus sclerosis (MTLE-HS) in humans. It has been demonstrated in this model that the phosphorylation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR1 subunit is increased 1 h after pilocarpine treatment. Moreover, alterations in the levels of glutamate transporters have been associated with chronic epilepsy in humans. Despite these studies, the profile of these changes has not yet been addressed. We analyzed the protein content and phosphorylation profile of the AMPA receptor GluR1 subunit by western blotting. We also used quantitative real-time polymerase chain reaction to analyze the expression of glial glutamate transporters and the N-methyl-d-aspartate receptor NR1 subunit in the hippocampus (Hip) and cerebral cortex (Ctx) at different time points after pilocarpine-induced status epilepticus (Pilo-SE) in male adult Wistar rats. Biochemical analysis was performed in the Hip and Ctx at 1, 3, 12 h (acute period), 5 days (latent period), and 50 days (chronic period) after Pilo-SE. Key findings include an increase in the phosphorylation of GluR1-Ser⁸⁴⁵ in the Ctx and GluR1-Ser⁸³¹ in the Hip at different times during the acute period, and a decrease in the total content of the GluR1 subunit in the Ctx in the latent period. There was a down-regulation of the mRNA expression and protein levels of EAAT1 and EAAT2, and a decrease of the NR1 mRNA expression, in the Ctx during the latent period. Notably, during the chronic period, the EAAT2 mRNA expression and protein levels decreased while the NR1 mRNA levels increased in the Hip. Taken together, our findings suggest a time- and structure-dependent imbalance of glutamatergic transmission in response to Pilo-SE, which might be associated with either epileptogenesis or the seizure threshold in MTLE-HS.