Pakistani children’s experiences of growing up with Beta-Thalassemia Major

In this study, we explored the lived experiences of children with beta-thalassemia major (β-TM). We considered children as experts on their experiences in contrast to the prevalent approach of asking parents or other adults about children’s perspectives. The sample consisted of 12 children aged 8 to12 years. There were two stages to data collection. In Stage 1 we employed two focus group discussions and two role plays and analyzed the data thematically. This directly informed Stage 2, consisting of 12 in-depth interviews subjected to interpretative phenomenological analysis. From our findings we show that living with β-TM involves a continuous struggle between feelings of being different and strategies to minimize these differences to strive for normalcy. We suggest that understanding the experiences of living with β-TM from children’s perspectives can provide unique insights into their experiences, which can fill the gap in the existing, predominantly adult-oriented research on chronic illness

Beta-thalassemia

Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 throughout the world and 1 in 10,000 people in the European Union. Three main forms have been described: thalassemia major, thalassemia intermedia and thalassemia minor. Individuals with thalassemia major usually present within the first two years of life with severe anemia, requiring regular red blood cell (RBC) transfusions. Findings in untreated or poorly transfused individuals with thalassemia major, as seen in some developing countries, are growth retardation, pallor, jaundice, poor musculature, hepatosplenomegaly, leg ulcers, development of masses from extramedullary hematopoiesis, and skeletal changes that result from expansion of the bone marrow. Regular transfusion therapy leads to iron overload-related complications including endocrine complication (growth retardation, failure of sexual maturation, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and less commonly, adrenal glands), dilated myocardiopathy, liver fibrosis and cirrhosis). Patients with thalassemia intermedia present later in life with moderate anemia and do not require regular transfusions. Main clinical features in these patients are hypertrophy of erythroid marrow with medullary and extramedullary hematopoiesis and its complications (osteoporosis, masses of erythropoietic tissue that primarily affect the spleen, liver, lymph nodes, chest and spine, and bone deformities and typical facial changes), gallstones, painful leg ulcers and increased predisposition to thrombosis. Thalassemia minor is clinically asymptomatic but some subjects may have moderate anemia. Beta-thalassemias are caused by point mutations or, more rarely, deletions in the beta globin gene on chromosome 11, leading to reduced (beta+) or absent (beta0) synthesis of the beta chains of hemoglobin (Hb). Transmission is autosomal recessive; however, dominant mutations have also been reported. Diagnosis of thalassemia is based on hematologic and molecular genetic testing. Differential diagnosis is usually straightforward but may include genetic sideroblastic anemias, congenital dyserythropoietic anemias, and other conditions with high levels of HbF (such as juvenile myelomonocytic leukemia and aplastic anemia). Genetic counseling is recommended and prenatal diagnosis may be offered. Treatment of thalassemia major includes regular RBC transfusions, iron chelation and management of secondary complications of iron overload. In some circumstances, spleen removal may be required. Bone marrow transplantation remains the only definitive cure currently available. Individuals with thalassemia intermedia may require splenectomy, folic acid supplementation, treatment of extramedullary erythropoietic masses and leg ulcers, prevention and therapy of thromboembolic events. Prognosis for individuals with beta-thalassemia has improved substantially in the last 20 years following recent medical advances in transfusion, iron chelation and bone marrow transplantation therapy. However, cardiac disease remains the main cause of death in patients with iron overload

LINC01605 Is a Novel Target of Mutant p53 in Breast and Ovarian Cancer Cell Lines

TP53 is the most frequently mutated gene in human cancers. Most TP53 genomic alterations are missense mutations, which cause a loss of its tumour suppressor functions while providing mutant p53 (mut_p53) with oncogenic features (gain-of-function). Loss of p53 tumour suppressor functions alters the transcription of both protein-coding and non-protein-coding genes. Gain-of-function of mut_p53 triggers modification in gene expression as well; however, the impact of mut_p53 on the transcription of the non-protein-coding genes and whether these non-protein-coding genes affect oncogenic properties of cancer cell lines are not fully explored. In this study, we suggested that LINC01605 (also known as lincDUSP) is a long non-coding RNA regulated by mut_p53 and proved that mut_p53 directly regulates LINC01605 by binding to an enhancer region downstream of the LINC01605 locus. We also showed that the loss or downregulation of LINC01605 impairs cell migration in a breast cancer cell line. Eventually, by performing a combined analysis of RNA-seq data generated in mut_TP53-silenced and LINC01605 knockout cells, we showed that LINC01605 and mut_p53 share common gene pathways. Overall, our findings underline the importance of ncRNAs in the mut_p53 network in breast and ovarian cancer cell lines and in particular the importance of LINC01605 in mut_p53 pro-migratory pathways

Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies

Objective: To correlate the density of swellings in intraepidermal nerve fibers (IENF) with the longitudinal measurement of the epidermal innervation density in patients with painful neuropathy and to assess the predictive value of IENF swelling to progression of neuropathy. Methods: Fifteen patients with persistent pain in the feet underwent neurologic examination, nerve conduction studies, quantitative sensory examination, and skin biopsies at proximal thigh and distal leg. In all patients and in 15 healthy subjects, IENF density and swelling ratio (no. swellings/no. IENF) were quantified at distal leg. Follow-up study, including IENF density and swelling ratio quantification, was performed a mean of 19.2 months later. Double staining confocal microscope studies using anti-human protein-gene-product 9.5, anti-tubule, anti-neurofilament, and anti-synaptophysin antibodies were performed to assess specific accumulation within swellings. Ultrastructural investigation of IENF was also carried out. Results: Patients with neuropathy had lower density of IENF and higher swelling ratio than healthy subjects (p<0.01) at distal leg. At follow-up, patients showed a parallel decrease in both IENF density (p=0.02) and swelling ratio (p=0.002). However, swelling ratio remained higher (p=0.03) than in controls. Progression of neuropathy was confirmed by the decay in sural nerve sensory nerve action potential amplitude. Double immunostaining studies suggest accumulation of tubules and ubiquitin-associated proteins within swellings. Swollen and vacuolated IENF were identified in patients with neuropathy by conventional and immuno-electron microscopy. Conclusions: Increased swelling ratio predicted the decrease in IENF density in patients with painful neuropathy. Its quantification could support earlier diagnosis of sensory axonopathy

Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with b-thalassemia

b-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with b-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non\u2013transfusion dependent (mean hemoglobin, &lt;10.0 g/dL; &lt;4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (\u20214 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for \u20215 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of \u20211.5 g/dL from baseline for \u202114 consecutive days (without RBC transfusions) for non\u2013transfusion-dependent patients or RBC transfusion burden reduction \u202120% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non\u2013transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase \u20211.5 g/dL over \u202114 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved \u202120% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of b-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as #NCT01749540 and #NCT02268409

The efficacy of iron chelator regimes in reducing cardiac and hepatic iron in patients with thalassaemia major: a clinical observational study

<p>Abstract</p> <p>Background</p> <p>Available iron chelation regimes in thalassaemia may achieve different changes in cardiac and hepatic iron as assessed by MR. The aim of this study was to assess the efficacy of four available iron chelator regimes in 232 thalassaemia major patients by assessing the rate of change in repeated measurements of cardiac and hepatic MR.</p> <p>Results</p> <p>For the heart, deferiprone and the combination of deferiprone and deferoxamine significantly reduced cardiac iron at all levels of iron loading. As patients were on deferasirox for a shorter time, a second analysis ("Initial interval analysis") assessing the change between the first two recorded MR results for both cardiac and hepatic iron (minimum interval 12 months) was made. Combination therapy achieved the most rapid fall in cardiac iron load at all levels and deferiprone alone was significantly effective with moderate and mild iron load. In the liver, deferasirox effected significant falls in iron load and combination therapy resulted in the most rapid decline.</p> <p>Conclusion</p> <p>With the knowledge of the efficacy of the different available regimes and the specific iron load in the heart and the liver, appropriate tailoring of chelation therapy should allow clearance of iron. Combination therapy is best in reducing both cardiac and hepatic iron, while monotherapy with deferiprone or deferasirox are effective in the heart and liver respectively. The outcomes of this study may be useful to physicians as to the chelation they should prescribe according to the levels of iron load found in the heart and liver by MR.</p

Development of the Thalassaemia Adult Life Index (ThALI)

Abstract: Background: Beta Thalassaemia Major (βTM) is a chronic genetic illness whereby the challenges faced by patients exposes them to increased risk of psychosocial issues. Despite this, a disease-specific tool to measure the impact of this illness on adult patients has yet to be developed. Methods: In collaboration with βTM adult patients, this study aimed to develop a comprehensive, disease-specific, easy to use psychometrically sound tool to measure the impact of chelation and transfusion dependent βTM in a cross-cultural patient group in England.The Thalassaemia Life Index (ThALI) was developed in two stages – item generation and pre-testing and item reduction – in collaboration with service users. Recruited adult patients shaped the design of the instrument including its statements and subscales. Standard item reduction techniques were used to develop the instrument. Results: The final version of the ThALI encompasses 35 statements and five sub-scales - general physical health, coping, body image, appearance and confidence, social relationships and autonomy. This endorses the multidimensionality of quality of life (QoL). The factor structure of the ThALI is highly stable and its internal consistency is high (alpha = 0.87 for the overall scale; 0.83–0.94 for its subscales). The ThALI has sound scaling assumptions, acceptability and score variability. Content validity was confirmed by experts and service user interviewees. The loadings for the items retained were adequate and the item discriminant validity sound. Conclusions: The ThALI covers the impact of βTM in adult patients. Preliminary testing shows its multidimensionality to be reliable and valid. The national authentication of the tool with patients treated in Centres of Excellence will aim to provide further evidence regarding the ThALI’s psychometric properties. Once authenticated, the ThALI may be utilised in research and in clinical settings to assess the effects of new therapies and/or interventions from the patients’ perspective to inform practice and/or to identify areas of concern

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Attenuated total reflection infrared spectroscopy for studying adsorbates on planar model catalysts : CO adsorption on silica supported Rh nanoparticles

A sensitive method is presented for studying adsorption of gaseous species on metal surfaces in vacuum by attenuated total internal reflection Fourier transform IR spectroscopy (ATR). The method is illustrated by CO adsorption expts. on silica supported Rh nanoparticles. An exptl. setup and a procedure are described in detail to obtain a sensitivity of reflectance change of .apprx.5 * 10-5 absorbance units. Here, a silicon ATR crystal with a 50 nm layer of hydroxylated silica acts as the support for the Rh nanoparticles. These particles are easily prepd. by spincoat impregnation from a RhCl3 soln. followed by H2 redn. XPS before and after redn. shows that rhodium is reduced to Rh0 and that all chlorine is removed. At. force microscope images the distribution of the particles, which are 3-4 nm in height. When the crystal is exposed to pressures up to 1 mbar of CO, a gas which is inert to the silica support, the stretch vibration of linearly adsorbed CO on the Rh nanoparticles is detected at 2023 cm-1, while no bridged CO or geminal dicarbonyl species can be distinguished. The min. detectable coverage is estd. .apprx.0.005 CO per nm2 substrate area or .apprx.5 * 10-4 ML. [on SciFinder (R)