Nataša Drača

Thyroid-stimulating hormone restores bone volume, microarchitecture, and strength in aged ovariectomized rats.

We show the systemic administration of low levels of TSH increases bone volume and improves bone microarchitecture and strength in aged OVX rats. TSHs actions are mediated by its inhibitory effects on RANKL‐induced osteoclast formation and bone resorption coupled with stimulatory effects on osteoblast differentiation and bone formation, suggesting TSH directly affects bone remodeling in vivo.

Systemically Administered Bone Morphogenetic Protein-6 Restores Bone in Aged Ovariectomized Rats by Increasing Bone Formation and Suppressing Bone Resorption

Although recombinant human bone morphogenetic proteins (BMPs) are used locally for treating bone defects in humans, their systemic effect on bone augmentation has not been explored. We have previously demonstrated that demineralized bone (DB) from ovariectomized (OVX) rats cannot induce bone formation when implanted ectopically at the subcutaneous site. Here we showed in vitro that 17β-estradiol (E2) specifically induced expression of Bmp6 mRNA in MC3T3-E1 preosteoblastic cells and that bone extracts from OVX rats lack BMPs. Next we demonstrated that 125I-BMP-6 administered systemically accumulated in the skeleton and also restored the osteoinductive capacity of ectopically implanted DB from OVX rats. BMP-6 applied systemically to aged OVX rats significantly increased bone volume and mechanical characteristics of both the trabecular and cortical bone, the osteoblast surface, serum osteocalcin and osteoprotegerin levels, and decreased the osteoclast surface, serum C-telopeptide, and interleukin-6. E2 was significantly less effective, and was not synergistic with BMP-6. Animals that discontinued BMP-6 therapy maintained bone mineral density gains for another 12 weeks. BMP-6 increased in vivo the bone expression of Acvr-1, Bmpr1b, Smad5, alkaline phosphatase, and collagen type I and decreased expression of Bmp3 and BMP antagonists, chordin and cerberus. These results show, for the first time, that systemically administered BMP-6 restores the bone inductive capacity, microarchitecture, and quality of the skeleton in osteoporotic rats.

Treatment of anti-vascular endothelial growth factor-resistant diabetic macular edema with dexamethasone intravitreal implant.

Purpose: To investigate the efficiency of intravitreal dexamethasone implant in patients with chronic diabetic macular edema nonresponsive to three consecutive monthly intravitreal injections of anti–vascular endothelial growth factor administered previously. Methods: Fifteen patients (16 eyes) were included in this 4-month prospective clinical trial. Main observed outcomes were the changes between initial and monthly visits in best-corrected visual acuity, central foveal thickness, and intraocular pressure (IOP). Patients included had central foveal thickness of >225 &mgr;m (measured by optical coherence tomography) and were nonresponsive to previously administered 3 consecutive monthly intravitreal injections of 1.25-mg bevacizumab. Administration of intravitreal dexamethasone implant was performed at baseline, and patients were followed-up monthly. Results: Statistically significant changes from baseline were observed in best-corrected visual acuity (at 2 months), central foveal thickness (at 1, 2, and 3 months), and IOP (at Months 1, 2, and 3) as follows: mean best-corrected visual acuity significantly increased from 0.29 Snellen lines at baseline to 0.39 lines after 2 months (P = 0.0381). At Months 1, 2, and 3, the mean central foveal thickness significantly decreased, from 462 &mgr;m at baseline, to 366 &mgr;m (P = 0.0343), 346 &mgr;m (P = 0.0288), and 355 &mgr;m (P = 0.0370), respectively. When compared with baseline IOP of 15.38 mmHg (12–19 mmHg), IOP increased significantly at Months 1, 2, and 3: 18.93 mmHg (range, 16–24 mmHg; P = 0.0003), 19.5 mmHg (range, 16–27 mmHg; P = 0.0003), and 17.5 mmHg (range, 15–21 mmHg; P = 0.0048), respectively. Conclusion: Dexamethasone intravitreal implant may present an alternative option in the treatment of chronic diabetic macular edema nonresponsive to three consecutive monthly bevacizumab injections administered previously. However, IOP measures were only slightly increased. It seems that the effect of dexamethasone may last till 4 months after initial injection.

Sevelamer Restores Bone Volume and Improves Bone Microarchitecture and Strength in Aged Ovariectomized Rats

Sevelamer hydrochloride, a noncalcium phosphate binder, has been shown to reduce coronary artery and aortic calcification, and to improve trabecular bone mineral density in hemodialysis patients with chronic kidney disease. Here, we examined whether sevelamer given orally for 12 wk with normal food could restore bone volume (BV) and strength in aged ovariectomized (OVX) rats starting at 4 wk after OVX. Dual-energy x-ray absorptiometry, microcomputerized tomography, and bone histomorphometry analyses showed that OVX animals receiving sevelamer had increased trabecular BV (51%), trabecular number (43%), trabecular thickness (9%), cortical thickness (16%), mineral apposition rate (103%), bone formation rate (25%), and enhanced cortical and trabecular bone mechanical strength as compared with OVX rats. Sevelamer decreased collagen C telopeptide, increased osteocalcin levels, and decreased phosphate and magnesium levels without affecting calcium levels in the blood. Although sevelamer was not absorbed systemically, it stimulated osteoblast differentiation in BM-derived mesenchymal stem cell cultures, as evaluated by alkaline phosphatase positive colony-forming units, and inhibited recombinant human soluble receptor activator of nuclear factor-kappaB ligand-induced osteoclast differentiation, as evaluated by tartrate-resistant acid phosphatase positive cells in bone mineral-hematopoietic stem cell cultures. Surface enhanced laser desorption/ionization time-of-flight mass spectrometry analysis revealed that 69 proteins were differently expressed after OVX, of which 30% (20 of 69) were reversed to sham activity after sevelamer intake. PTH, fibroblast growth factor-23, and cytokine profile in serum were not significantly changed. Together, these results suggest that sevelamer in food increases the BV and improves biomechanical properties of bone in OVX rats.

TSH prevents bone resorption and with calcitriol synergistically stimulates bone formation in rats with low levels of calciotropic hormones.

Thyroid-stimulating hormone exerts both antiresorptive and anabolic effects on bone remodeling in aged ovariectomized rats and thyroid stimulating hormone-receptor null mice, supported by clinical results demonstrating that low thyroid-stimulating hormone level is associated with increased bone loss. To further explore the effect of thyroid-stimulating hormone on bone metabolism we introduced here a rat model with removed thyroid and parathyroid glands to obtain low serum concentrations of thyroid and parathyroid hormone, calcitonin and 1,25(OH)2D3. Surgery resulted in hypocalcemia, low parathyroid and thyroid hormone, 1,25(OH)2D3, C-telopeptide, and osteocalcin serum level. Intermittent administration of thyroid-stimulating hormone resulted in a further decrease of serum calcium and decreased level of serum C-telopeptide due to the suppression of bone resorption, while in the same animals osteocalcin in serum was higher indicating an increased bone formation rate. A combination of thyroid-stimulating hormone and 1,25(OH)2D3 significantly increased the serum Ca2+, C-telopeptide and serum osteocalcin values. MicroCT analyses of the distal femur and proximal tibia showed that rats treated with 1,25(OH)2D3 alone or in a combination with thyroid-stimulating hormone had an increased trabecular bone volume, and enhanced trabecular bone quality. Biomechanical testing of the trabecular bone showed an increased maximal load for 105% and 235%, respectively, in rats treated with 1,25(OH)2D3 alone, or in a combination with thyroid-stimulating hormone. We suggest that thyroid-stimulating hormone independently of calciotropic hormones suppressed bone resorption and stimulated bone formation, while in combination with 1,25(OH)2D3 acted synergistically on bone formation resulting in an increased bone volume.

Potential beneficial role of sevelamer hydrochloride in diabetic retinopathy

Patients with chronic kidney disease (CKD) experience co-morbid illnesses, including cardiovascular disease and retinopathy. Sevelamer hydrochloride (Renagel®); a non-calcium phosphate binder reduces coronary artery and aortic calcification as compared to calcium containing phosphate binders and additionally effects inflammatory biomarkers such as C-reactive protein (CRP), and lowers LDL cholesterol in patients with CKD. Since retinopathy is proven to be associated with increased coronary calcification, shared pathophysiological processes may contribute to both microvascular and macrovascular disease. We here suggest three different mechanisms of possible sevelamers influence on the retinopathy: (1) by direct effect on the microvasculature through lowering CRP and LDL, involved in endothelial dysfunction and atherogenesis, (2) indirectly by attenuation of vascular calcification of aorta and carotid internal artery, it reduces ischaemia and improves circulation in the opthalmic artery and hence postponing retinopathy, (3) through hypertension by reducing atherosclerosis and calcification of carotid arteries, sevelamer decreases stiffness and intima-media wall thickness, therefore lowering blood pressure, which is well known to increase progression of diabetic retinopathy. So far no studies have yet been published on the direct influence of sevelamer on the retinopathy which we believe has good theoretical background. With its combined macrovascular and microvascular effect, sevelamer could potentially postpone and/or decrease retinopathy in diabetic patients with hypertension, and that are on hemodialysis or even predialysis patients.

Comparison of Verisyse and Veriflex Phakic Intraocular Lenses for Treatment of Moderate to High Myopia 36 Months after Surgery

ABSTRACT Purpose: To compare refractive stability, endothelial cell count (ECC), incidence of complications, and patients’ satisfaction between a rigid Verisyse (group I, n = 198) and foldable Veriflex (group II, n = 212) phakic intraocular lenses (pIOL) over 36 months postop. Materials and methods: This was a retrospective study. Patients’ satisfaction and incidence of photic phenomena were evaluated at one month and one year postop. Data were analyzed to determine difference between groups for astigmatism, mean spherical equivalent (MRSE), uncorrected (UDVA) and corrected (CDVA) monocular distance visual acuity, complication rate (acute and chronic), and ECC. Differences were considered statistically significant when p < 0.05. Results: Group II cases had significantly higher UDVA, CDVA, and lower astigmatism during the entire follow-up. There was no significant difference in mean MRSE or mean ECC postoperatively. In both groups, mean ECC reduced significantly at one month postop, followed by a gradual linear decline between 1 and 36 months of 22.4 cells/mm2/annum (group I) and 13.32 cells/mm2/annum (group II). Overall complication rates were ≤ 10% with no significant inter-group differences. Group I patients reported lower incidence of halos at one month but more problems with night vision at one year compared with group II. Overall satisfaction was high and total incidence of reported photic phenomena was low. Conclusion: Both Verisyse and Veriflex pIOLs are effective in correcting myopia. The Veriflex lens demonstrated better refractive outcome; however, subclinical inflammation observed in the Veriflex group and potential influence of inflammation on ECC loss require further investigation.

Positive pressure during penetrating keratoplasty can be solved with a modified graft-over-host technique

Purpose:  To describe a modified graft‐over‐host (MGOH) surgical technique which was used to prevent serious complications in cases of positive vitreal pressure during penetrating keratoplasty (PKP) and to compare the endothelial cell density (ECD) loss and clinical outcome between eyes undergoing MGOH or standard PKP.

Autologous Neurosensory Retinal Free Flap Treatment for a Large Macular Hole

A patient presented with a large chronic macular hole (MH) of 700 μm. Best-corrected visual acuity (BCVA) was 20/200. Since the MHs edges were attached and stiff, an autologous neurosensory retinal flap was harvested and placed into the MH to close it. Perfluoro-n-octane heavy liquid (PFC) was instilled over the flap and exchanged with silicone oil (1,000 cs). Seven days postoperatively, the MH was closed, with a BCVA of 20/80 that improved to 20/60 at months 1 and 3. Optical coherence tomography and angiography showed patch incorporation with fovea formation and normal circulation. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e89-e92.].

Use of bevacizumab (anti-VEGF treatment) in high-risk corneal grafts

Purpose We evaluated the effect of bevacizumab treatment in a prospective 2 year follow‐up study of 50 [bdquo]high risk“ eyes undergoing penetrating keratoplasty (PKP).