A Novel Antigen Sensitive to Calcium Chelation That is Associated with the Tip Links and Kinocilial Links of Sensory Hair Bundles

Tip links are extracellular, cell-surface-associated filaments of unknown molecular composition that are thought to gate the mechanotransducer channel of the sensory hair cell. They disappear from the hair bundle in response to calcium chelation and lanthanum treatment and resist degradation by the protease subtilisin. A monoclonal antibody derived from a hybridoma screen identified a novel antigen associated with tip links, the tip-link antigen. The tip-link antigen is also associated with kinocilial links, subtilisin-resistant filaments that are sensitive to calcium chelation and connect the kinocilium to the tallest stereocilia of the hair bundle. Furthermore, the tip-link antigen is expressed in the retina, where it is associated with the ciliary calyx, a ring of microvilli that surrounds the outer segment of the photoreceptor. The tip-link antigen rapidly disappears from the surface of the hair bundle in response to calcium chelation. It is also subtilisin resistant, relative to the ankle-link antigen, an antigen associated with another type of hair bundle link. The tip-link antigen is lanthanum sensitive and, like tip links, reappears on the surface of the hair bundle after calcium chelation. The monoclonal antibody to the tip-link antigen immunoprecipitates two concanavalin A-reactive polypeptides with apparent molecular masses of 200 and 250 kDa from detergent extracts of the retina. These results provide the first identification of a cell surface antigen associated with tip links, indicate that tip links share properties in common with kinocilial links, and reveal a second epitope that, along with the ankle-link antigen, is common to both sensory hair bundles and the ciliary calyx of photoreceptors

Comparative efficacy of deferiprone, deferoxamine and combination of deferiprone and deferoxamine on serum ferritin value in Beta-Thalassemia patients

Background: Iron overload is a predictable and life-threatening complication in patients with thalassemia. Effective and convenient iron chelation remains one of the main targets of clinical management of thalassemia major. The development of a safe and effective chelator has been the goal for many years. Aims and Objective: It was aimed to compare the effect of deferiprone, deferoxamine and combination of deferiprone and deferoxamine on serum ferritin value in beta-thalassemia patients. Material and Methods: This controlled clinical trial was conducted on 46 major beta-thalassemic patients. Fifteen patients in deferiprone group received deferiprone 75mg/kg/day three times a day orally. Nineteen patients in deferoxamine group received deferoxamine 30-50 mg/kg/day subcutaneously for 8-12 hours/day and 5 days per week. Twelve patients in combined therapy group received deferiprone 75 mg/kg/day three times a day orally with deferoxamine 30–50 mg/kg subcutaneously every other day. Serum ferritin value was measured at the beginning and at the end of 6th and 12th months of study. Results: The mean of serum ferritin value in deferiprone group insignificantly increased from 2731± 1398.5 μg/L at the beginning to 2788.5 ± 978.6 μg/L and to 3331.8 ± 1833.9 μg/L at the end of 6th and 12th months of study, respectively. The mean of serum ferritin value in deferoxamine group insignificantly increased from 2883.5 ± 1598.1 μg/L at the beginning to 2935.3 ± 1258.2 μg/L at the end of 6th month of study and decreased to 2773.8 ± 1216.1 μg/L and 12th month of study. The mean of serum ferritin level in combined therapy group significantly decreased from 7498.7 ± 3512.9 μg/L at the beginning to 4839.9 ± 2698.2 μg/L (P < 0.001) and to 4298.2 ± 2288.7 μg/L (P < 0.001) at the end of 6th and 12th months of study, respectively. Conclusion: Combined therapy significantly decreases serum ferritin level. Study suggests deferiprone as a significant addition to support therapy in patients with betathalassemia major on regular transfusion regimens. © 2015 Journal of Krishna Institute of Medical Sciences University

How early can myocardial iron overload occur in Beta thalassemia major?

BACKGROUND: Myocardial siderosis is the most common cause of death in patients with beta thalassemia major(TM). This study aimed at investigating the occurrence, prevalence and severity of cardiac iron overload in a young Chinese population with beta TM. METHODS AND RESULTS: We analyzed T2* cardiac magnetic resonance (CMR), left ventricular ejection fraction (LVEF) and serum ferritin (SF) in 201 beta TM patients. The median age was 9 years old. Patients received an average of 13 units of blood per year. The median SF level was 4536 ng/ml and 165 patients (82.1%) had SF>2500 ng/ml. Myocardial iron overload was detected in 68 patients (33.8%) and severe myocardial iron overload was detected in 26 patients (12.6%). Twenty-two patients ≤10 years old had myocardial iron overload, three of whom were only 6 years old. No myocardial iron overload was detected under the age of 6 years. Median LVEF was 64% (measured by CMR in 175 patients). Five of 6 patients with a LVEF<56% and 8 of 10 patients with cardiac disease had myocardial iron overload. CONCLUSIONS: The TM patients under follow-up at this regional centre in China patients are younger than other reported cohorts, more poorly-chelated, and have a high burden of iron overload. Myocardial siderosis occurred in patients younger than previously reported, and was strongly associated with impaired LVEF and cardiac disease. For such poorly-chelated TM patients, our data shows that the first assessment of cardiac T2* should be performed as early as 6 years old

Spontaneous Chelation-Driven Reduction of the Neptunyl Cation in Aqueous Solution.

Octadentate hydroxypyridinone (HOPO) and catecholamide (CAM) siderophore analogues are known to be efficacious chelators of the actinide cations, and these ligands are also capable of facilitating both activation and reduction of actinyl species. Utilizing X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) spectroscopies, as well as cyclic voltammetry measurements, herein, we elucidate chelation-based mechanisms for driving reactivity and initiating redox processes in a family of neptunyl-HOPO and CAM complexes. Based on the selected chelator, the ability to control the oxidation state of neptunium and the speed of reduction and concurrent oxo group activation was demonstrated. Most notably, reduction kinetics for the NpV O2 +/ /NpIV redox couple upon chelation by the ligands 3,4,3-LI(1,2-HOPO) and 3,4,3-LI(CAM)2 (1,2-HOPO)2 was observed to be faster than ever reported, and in fact quicker than we could measure using either X-ray absorption spectroscopy or electrochemical techniques

The use or misuse of biomedical treatment approaches to autism

Introduction: The need for evidence based recommendations regarding biomedical approaches to autism was felt in view of the significant number of autistic children presenting within the Child Development Assessment Unit, Malta and the interest shown in these approaches by their families and local nongovernmental organisations. Aim: To establish the medical basis of biomedical approaches to treating autism, by establishing which of these approaches are of reported proven efficacy, effectiveness and safety and hence offer recommendations for their use. Methods: An electronic literature search was carried out for supporting evidence-based biomedical approaches in autism, particularly mainstream authoritative national guidelines. Results: No strong recommendation was found to support any of the biomedical approaches to autism addressed in 10 authoritative national guidelines from 1999 to 2011. The evidence and recommendations were against using chelation, immunoglobulin therapy, secretin, amantadine, antifungal/yeast therapies, naltrexone, dimethylglycine, vancomycin, digestive enzyme supplements and donepezil. Melatonin for sleep disturbances and to a lesser degree, Omega-3 fatty acids for hyperactivity had enough support to consider their use in autism. The recommendations for gluten/casein diets, and Vitamin B6/magnesium were mostly either indeterminate or negative. Iron, vitamin C, piracetam, pentoxifylline, ketogenic diets, L-carnosine and hyperbaric oxygen therapy could not be safely recommended. Conclusion: The evidence-based literature does not support most biomedical approaches to autism. There is limited support for melatonin and Omega-3 use.peer-reviewe

Full Sequence Bleaching with Dimethyldioxirane

Research work to date has shown dimethyldioxirane to be a very powerful, yet highly selective oxidant. Dimethyldioxirane bleaching may become more important in the future with legislative restrictions on chlorine based bleaching agents as it contains no chlorine. Most work with dimethyldioxirane to date has concentrated on short sequence bleaching, or the use of peroxymonosulfate as a pre-treatment to improve oxygen delignification. The goal of this study was to develop a full sequence bleaching containing only dimethyldioxirane and other chlorine free bleaching agents that matched the brightness and strength characteristics of comparable chlorine dioxide based full sequences. Dimethyldioxirane was found to match the strength, but not the brightness of, chlorine dioxide. As well, dimethyldioxirane may be harsher on cellulose than chlorine dioxide. Additional optimization may allow dimethyldioxirane to perform as well as chlorine dioxide. It was seen that increased brightnesses were achieved by using optimum conditions and a step-wise chemical addition. As well, the addition of peroxide to dimethyldioxirane stages may increase brightness

ADVANCING THE SEPARATION SCIENCES THROUGH THE DELIVERY OF NEW MATERIALS, TECHNOLOGY AND METHODOLOGY.

A thesis and collection of works submitted to Plymouth University in partial fulfilment for the degree of DOCTOR OF SCIENC

Chelator-facilitated removal of iron from transferrin: Relevance to combined chelation therapy

Current iron chelation therapy consists primarily of DFO (desferrioxamine), which has to be administered via intravenous infusion, together with deferiprone and deferasirox, which are orally-active chelators. These chelators, although effective at decreasing the iron load, are associated with a number of side effects. Grady suggested that the combined administration of a smaller bidentate chelator and a larger hexadentate chelator, such as DFO, would result in greater iron removal than either chelator alone [Grady, Bardoukas and Giardina (1998) Blood 92, 16b]. This in turn could lead to a decrease in the chelator dose required. To test this hypothesis, the rate of iron transfer from a range of bidentate HPO (hydroxypyridin-4-one) chelators to DFO was monitored. Spectroscopic methods were utilized to monitor the decrease in the concentration of the Fe–HPO complex. Having established that the shuttling of iron from the bidentate chelator to DFO does occur under clinically relevant concentrations of chelator, studies were undertaken to evaluate whether this mechanism of transfer would apply to iron removal from transferrin. Again, the simultaneous presence of both a bidentate chelator and DFO was found to enhance the rate of iron chelation from transferrin at clinically relevant chelator levels. Deferiprone was found to be particularly effective at ‘shuttling’ iron from transferrin to DFO, probably as a result of its small size and relative low affinity for iron compared with other analogous HPO chelators