COX-2 expression in chondrosarcoma: A role for celecoxib treatment?

Chondrosarcomas are resistant to conventional chemo- and radiotherapy. A subset of chondrosarcomas arises secondarily in the benign tumour syndromes enchondromatosis (EC) and multiple osteochondromas (MO), and prevention of tumour development would greatly improve prognosis. We therefore investigated the effect of selective COX-2 inhibition on chondrosarcoma growth.COX-2 expression was studied in central- and peripheral cartilaginous tumours. The effect of COX-2 inhibition was assessed in four high-grade chondrosarcoma cell lines using celecoxib and NS-398 treatment. COX-2 activity (prostaglandin E₂ (PGE₂) ELISA) and cell viability were measured. The (prophylactic) effect of celecoxib on chondrosarcoma growth in vivo was studied for 8 weeks using a xenograft model of cell line CH2879 in immunoincompetent nude mice.High COX-2 protein expression was mainly found in solitary peripheral chondrosarcoma and in enchondromatosis-related central chondrosarcoma, which was confirmed by qPCR. After 72 h of celecoxib treatment, a significant decrease in cell viability was observed in three chondrosarcoma cell lines. In vivo, celecoxib initially slowed tumour growth in chondrosarcoma xenografts; however, after prolonged treatment relapsed tumour growth was observed. Tumour volume was negatively associated with celecoxib serum levels, and seemed smaller in the high-dose prophylactic treatment group.We confirmed the expression of COX-2 in 65% of chondrosarcomas, and COX-2 inhibition by celecoxib diminished cell viability in vitro. The initial response and the decrease in tumour volume with increased celecoxib serum levels in vivo supported a role for celecoxib, although relapsed tumour growth after 6 weeks was worrisome. Also the role of high-dose prophylactic celecoxib in preventing the development of benign and malignant cartilage tumours in EC and MO patients deserves further investigation.     

Bilaterale Hornhautulzera mit Hypopyon und Exitus letalis

Ohne Zusammenfassung     

Persistent indocyanine green (ICG) fluorescence 6 weeks after intraocular ICG administration for macular hole surgery

BACKGROUND: Macular hole surgery including vitrectomy and peeling of epiretinal membranes and the internal limiting membrane (ILM) has become a standard procedure in retinal surgery. Poor visualization of epiretinal membranes and the ILM is an obstacle to successful surgery. Recently, indocyanine green (ICG) has been reported to be a helpful intraocular substance in identifying these membranes. METHODS: In a case of stage IV macular hole, epiretinal membranes and ILM were intraoperatively stained with three drops of 1:9 diluted ICG. After 1 min incubation the vitreous cavity was rinsed with Ringer's lactate solution, and the membranes were peeled. Autologous thrombocytes were applied to the macular hole, and the eye was endotamponaded with 20% SF6 gas. Six weeks postoperatively, visual acuity was measured and fundus photographs and autofluorescence images, as well as a multifocal ERG, were obtained. RESULTS: Intraoperatively, the ILM could be nicely visualized by ICG, which allowed immediate peeling. Six weeks after surgery, the visual acuity had improved from 0.1 to 0.7 and the macular hole was closed. Autofluorescence imaging at 795 nm revealed a strong signal. Multifocal ERG recording showed regular amplitudes. CONCLUSION: ICG as an intraocular tool for staining of the ILM is helpful in macular hole surgery. We did not observe any negative effect on retinal function; however, we were surprised to identify traces of ICG in retinal fluorescein angiography images 6 weeks postoperatively.     

Association between a hospitalization for heart failure and the initiation/discontinuation of guideline-recommended treatments: An analysis from the Swedish Heart Failure Registry

Aims

To investigate whether a heart failure (HF) hospitalization is associated with initiation/discontinuation of guideline-directed medical HF therapy (GDMT) and consequent outcomes.

Methods and results

Among patients in the Swedish HF registry with an ejection fraction <50% enrolled in 2009–2018, initiation/discontinuation of GDMT was investigated by assessing dispensations of GDMT in those with versus without a HF hospitalization. Of 14 737 patients, 6893 (47%) were enrolled when hospitalized for HF. Initiation of GDMT was more likely than discontinuation following a HF hospitalization compared to a control group of patients without a HF hospitalization (odds ratio range 2.1–4.0 vs. 1.4–1.6 for the individual medications), although the proportion of patients not on GDMT was still high (8.1–44.0%). Key patient characteristics triggering less use of GDMT (i.e. less initiation or more discontinuation) were older age and worse renal function. Following a HF hospitalization, initiation of renin–angiotensin system inhibitors/angiotensin receptor–neprilysin inhibitors or beta-blockers was associated with lower and their discontinuation with higher mortality risk, but no association with mortality was observed for initiation/discontinuation of mineralocorticoid receptor antagonists.

Conclusions

Following a HF hospitalization, initiation of GDMT was more likely than discontinuation, although still limited. Perceived or actual low tolerance were barriers to GDMT implementation. Early re-/initiation of GDMT was associated with better survival. Our findings represent a call for further implementing the current guideline recommendation for an early re-/initiation of GDMT following a HF hospitalization.     

Rotator cuff tears: preliminary application of high-resolution MR imaging with counter rotating current loop-gap resonators

A new class of radio frequency (RF) coils for magnetic resonance (MR) imaging and spectroscopy is introduced. The coils consist of two loop-gap resonators of equal diameters positioned along a common axis. They are tuned to the mode in which the current in the two loops flows in opposite directions. These coils are "decoupled" from a uniform excitation field of arbitrary orientation (including circularly polarized fields) by intrinsic decoupling and by means of back-to-back fast recovery diodes. Measurements made with the coils and a phantom saline tank indicate that the signal-to-noise ratio obtainable with these coils is almost identical to that obtained with single loops. Imaging of several anatomic areas, including knee, wrist, and shoulder, has been performed with a 1.5-T MR system that uses circularly polarized RF. A small series of patients with torn rotator cuffs underwent imaging. Difficulties in establishing the diagnosis with MR imaging because of anatomic complexity are illustrated. The value of pulse sequences with long repetition times to increase the signal intensity of fluid in the joint is shown.     

Conjunctival tissue examination in severe eye burns: a study with scanning electron microscopy and energy-dispersive X-ray analysis

Background: Longlasting inflammation is a major problem in treatment after severe eye burns and may find expression in an altered elemental composition of the conjunctiva. Particulate contamination of biological tissue induces such inflammatory processes. In the anterior eye segment, trauma or subsequent therapy may give rise to such contamination. Scanning electron microscopy and energy-dispersive X-ray analysis are able to detect traumatic residues of submicron size and changes of the elemental composition.Methods: Conjunctival specimens from first-time peridectomy of three healthy and nine severely burnt-eyes were examined with scanning electron microscopy and energy-dispersive X-ray analysis. The samples were prepared as cryo- or paraffin sections, mounted on carbon blocks and coated with evaporated elemental carbon.Results: The samples of healthy conjunctiva showed higher concentrations of Na, P and CI. These elements showed lower concentrations in conjunctival stroma of burnt eyes excised before the 20th day after trauma than in material obtained subsequently. In two burnt conjunctival specimens there was severe traumatic contamination with Ca in Ca(OH)₂ and CaO burns, and in one case the traumatic substance was Si, in a peroxide plus silicone spray burn. In the remaining six cases, particulate contamination with Fe, Al, Ni, Zn, Cu, Ti and other substances was present in the burnt conjunctivas, while no contamination was detected in the specimens of healthy conjunctivas.Conclusions: The origin of the contaminant particles is assumed to be the trauma itself and the subsequent therapy. These investigations stress the importance, for clinical purposes, or early peridectomy and contamination-free therapy.     

Effects of ascorbic acid on retinal pigment epithelial cells.

PURPOSE: Evaluation of effects of ascorbic acid on cell characteristics of dedifferentiated porcine retinal pigment epithelial (pRPE) cells. METHODS: pRPE cells were incubated in vitro with increasing concentrations of ascorbic acid (0.25-1.5 mMol). Cell proliferation was assayed by measuring the incorporation of 5-bromo-2'-deoxy-uridine (BrdU) into cellular DNA. Migration and contraction properties were studied on a cell permissive porous membrane and collagen gels, respectively. Phenotypic changes in response to ascorbic acid and its derivative ascorbic acid 2-phophate were evaluated by microscopy and indirect immunofluorescence. RESULTS: Ascorbic acid significantly inhibits cell proliferation, migration, and contraction in concentrations of 1 mMol or more. Under the influence of at least 1 mMol ascorbic acid dedifferentiated pRPE cells exhibited a pigmented status within 24 hours. Addition of 500 U/ml catalase prevented the antiproliferative effect of ascorbic acid and the formation of pigment. Concentrations of 0.5 mMol ascorbic acid as well as 1 mMol ascorbic acid 2-phosphate promoted differentiation of cell phenotype. Furthermore, ascorbic acid 2-phosphate supported the formation of in vivo-like epithelial structures. CONCLUSIONS: Ascorbic acid has an influence on vital cell characteristics such as proliferation, migration, contraction and differentiation of pRPE cells. As dedifferentiation of these cells is an integral part in the development of proliferative vitreoretinopathy (PVR), ascorbic acid should be taken into consideration as a supplement in the clinical management of this disease.     

Deferiprone (L1) chelates pathologic iron deposits from membranes of intact thalassemic and sickle red blood cells both in vitro and in vivo

Red blood cell (RBC) membranes from patients with the thalassemic and sickle hemoglobinopathies carry abnormal deposits of iron presumed to mediate a variety of oxidative-induced membrane dysfunctions. We hypothesized that the oral iron chelator deferiprone (L1), which has an enhanced capacity to permeate cell membranes, might be useful in chelating these pathologic iron deposits from intact RBCs. We tested this hypothesis in vitro by incubating L1 with RBCs from 15 patients with thalassemia intermedia and 6 patients with sickle cell anemia. We found that removal of RBC membrane free iron by L1 increased both as a function of time of incubation and L1 concentration. Thus, increasing the time of incubation of thalassemic RBCs with 0.5 mmol/L L1 from 0.5 to 6 hours, enhanced removal of their membrane free iron from 18% +/- 9% to 96% +/- 4%. Dose-response studies showed that incubating thalassemic RBC for 2 hours with L1 concentrations ranging from 0.125 to 0.5 mmol/L resulted in removal of membrane free iron from 28% +/- 15% to 68% +/- 11%. Parallel studies with sickle RBCs showed a similar pattern in time and dose responses. Deferoxamine (DFO), on the other hand, was ineffective in chelating membrane free iron from either thalassemic or sickle RBCs regardless of dose (maximum, 0.333 mmol/L) or time of incubation (maximum, 24 hours). In vivo efficacy of L1 was shown in six thalassemic patients whose RBC membrane free iron decreased by 50% +/- 29% following a 2-week course of L1 at a daily dose of 25 mg/kg. As the dose of L1 was increased to 50 mg/kg/d (n = 5), and then to 75 mg/kg/d (n = 4), 67% +/- 14% and 79% +/- 11%, respectively, of their RBC membrane free iron was removed. L1 therapy-- both in vitro and in vivo--also significantly attenuated the malondialdehyde response of thalassemic RBC membranes to in vitro stimulation with peroxide. Remarkably, the heme content of RBC membranes from L1-treated thalassemic patients decreased by 28% +/- 10% during the 3-month study period. These results indicate that L1 can remove pathologic deposits of chelatable iron from thalassemic and sickle RBC membranes, a therapeutic potential not shared by DFO. Furthermore, membrane defects possibly mediated by catalytic iron, such as lipid peroxidation and hemichrome formation, may also be alleviated, at least in part, by L1.