Thalassemia bone disease is a common and severe complication of thalassemia—an inherited blood disorder due to mutations in the α or β hemoglobin gene. In its more severe form, severe anemia is ...present, and treatment with frequent red blood cell transfusion is necessary. Because the body has limited capacity to excrete iron, concomitant iron chelation is required to prevent the complications of iron overload. The effects of chronic anemia and iron overload can lead to multiple end-organ complications such as cardiomyopathy, increased risks of blood-borne diseases, and liver, pituitary, and bone disease. However, our understanding of thalassemia bone disease is incomplete and is composed of a complex piecemeal of risk factors that include genetic factors, hormonal deficiency, marrow expansion, skeletal dysmorphism, iron toxicity, chelators, and increased bone turnover. The high prevalence of bone disease in transfusion-dependent thalassemia is seen in both younger and older patients as life expectancy continues to improve. Indeed, hypogonadism and GH deficiency contribute to a failure to achieve peak bone mass in this group. The contribution of kidney dysfunction to bone disease in thalassemia is a new and significant complication. This coincides with studies confirming an increase in kidney stones and associated accelerated bone loss in the thalassemia cohort. However, multiple factors are also associated with reduced bone mineral density and include marrow expansion, iron toxicity, iron chelators, increased bone turnover, GH deficiency, and hypogonadism. Thalassemia bone disease is a composite of not only multiple hormonal deficiencies but also multiorgan diseases. This review will address the molecular mechanisms and clinical risk factors associated with thalassemia bone disease and the clinical implications for monitoring and treating this disorder.
Plastic bronchitis is a potentially fatal disorder occurring in children with single-ventricle physiology, and other diseases, as well, such as asthma. In this study, we report findings of abnormal ...pulmonary lymphatic flow, demonstrated by MRI lymphatic imaging, in patients with plastic bronchitis and percutaneous lymphatic intervention as a treatment for these patients.
This is a retrospective case series of 18 patients with surgically corrected congenital heart disease and plastic bronchitis who presented for lymphatic imaging and intervention. Lymphatic imaging included heavy T2-weighted MRI and dynamic contrast-enhanced magnetic resonance lymphangiogram. All patients underwent bilateral intranodal lymphangiogram, and most patients underwent percutaneous lymphatic intervention. In 16 of 18 patients, MRI or lymphangiogram or both demonstrated retrograde lymphatic flow from the thoracic duct toward lung parenchyma. Intranodal lymphangiogram and thoracic duct catheterization was successful in all patients. Seventeen of 18 patients underwent either lymphatic embolization procedures or thoracic duct stenting with covered stents to exclude retrograde flow into the lungs. One of the 2 patients who did not have retrograde lymphatic flow did not undergo a lymphatic interventional procedure. A total of 15 of 17(88%) patients who underwent an intervention had significant symptomatic improvement at a median follow-up of 315 days (range, 45-770 days). The most common complication observed was nonspecific transient abdominal pain and transient hypotension.
In this study, we demonstrated abnormal pulmonary lymphatic perfusion in most patients with plastic bronchitis. Interruption of the lymphatic flow resulted in significant improvement of symptoms in these patients and, in some cases, at least temporary resolution of cast formation.
The investigators recently validated a method of quantifying systemic–to–pulmonary arterial collateral flow using phase-contrast magnetic resonance imaging velocity mapping. Cross-sectional data ...suggest decreased collateral flow in patients with total cavopulmonary connections (TCPCs) compared with those with superior cavopulmonary connections (SCPCs). However, no studies have examined serial changes in collateral flow from SCPCs to TCPCs in the same patients. The aim of this study was to examine differences in collateral flow between patients with SCPCs and those with TCPCs. Collateral flow was quantified by 2 independent measures from 250 single-ventricle studies in 219 different patients (115 SCPC and 135 TCPC studies, 31 patients with both) and 18 controls, during routine studies using through-plane phase-contrast magnetic resonance imaging. Collateral flow was indexed to body surface area, aortic flow, and pulmonary venous flow. Regardless of indexing method, SCPC patients had significantly higher collateral flow than TCPC patients (1.64 ± 0.8 vs 1.03 ± 0.8 L/min/m2 , p <0.001). In 31 patients who underwent serial examinations, collateral flow as a fraction of aortic flow increased early after TCPC completion. In TCPC patients, indexed collateral flow demonstrated a significant negative correlation with time from TCPC. In conclusion, SCPC and TCPC patients demonstrate substantial collateral flow, with SCPC patients having higher collateral flow than TCPC patients overall. On the basis of the paired subset analysis, collateral flow does not decrease in the short term after TCPC completion and trends toward an increase. In the long term, however, collateral flow decreases over time after TCPC completion.
First-line cancer treatments successfully eradicate the differentiated tumour mass but are comparatively ineffective against cancer stem cells (CSCs), a self-renewing subpopulation thought to be ...responsible for tumour initiation, metastasis, heterogeneity, and recurrence. CSCs are thus presented as the principal target for elimination during cancer treatment. However, CSCs are challenging to drug target because of numerous intrinsic and extrinsic mechanisms of drug resistance. One such mechanism that remains relatively understudied is the DNA damage response (DDR). CSCs are presumed to possess properties that enable enhanced DNA repair efficiency relative to their highly proliferative bulk progeny, facilitating improved repair of double-strand breaks induced by radiotherapy and most chemotherapeutics. This can occur through multiple mechanisms, including increased expression and splicing fidelity of DNA repair genes, robust activation of cell cycle checkpoints, and elevated homologous recombination-mediated DNA repair. Herein, we summarise the current knowledge concerning improved genome integrity in non-transformed stem cells and CSCs, discuss therapeutic opportunities within the DDR for re-sensitising CSCs to genotoxic stressors, and consider the challenges posed regarding unbiased identification of novel DDR-directed strategies in CSCs. A better understanding of the DDR mediating chemo/radioresistance mechanisms in CSCs could lead to novel therapeutic approaches, thereby enhancing treatment efficacy in cancer patients.
Objectives
Characterize the safety and effectiveness of the Amplatzer Piccolo Occluder for patent ductus arteriosus (PDA) closure.
Background
The presence of a hemodynamically significant PDA has ...been associated with an increased risk of morbidity and mortality in children born premature.
Methods
This was a single arm, prospective, multicenter, non‐randomized study to evaluate the Amplatzer Piccolo Occluder to treat PDA in patients ≥700 g. From June 2017 to February 2019, 200 patients were enrolled at nine centers, with 100 patients weighing ≤2 kg. Primary effectiveness endpoint was the rate of PDA closure at 6‐month follow‐up. Primary safety endpoint was the rate of major complications through 6 months. Secondary endpoint was rate of significant pulmonary or aortic obstruction through 6 months' follow‐up.
Results
The implant success rate was 95.5% (191/200) overall and 99% in patients ≤2 kg (99/100). The primary effectiveness endpoint was achieved in 99.4% of implanted patients. Four patients experienced a primary safety endpoint event (2 transfusions, 1 hemolysis, and 1 aortic obstruction). There were no branch pulmonary artery obstructions. Five patients, all ≤2 kg, were noted to have worsening of tricuspid regurgitation (TR) after the procedure. None of the TR incidences manifested clinically. The Amplatzer Piccolo Occluder received FDA approval in January 2019 and became the first device approved for PDA closure in patients ≥700 g.
Conclusions
This study supports the safety and effectiveness of the Amplatzer Piccolo Occluder, particularly in patients between 700 g and 2 kg where there is currently a significant unmet need in the United States. ClinicalTrials.gov identifier: NCT03055858.
Effective osteoporosis therapy requires agents that increase the amount and/or quality of bone. Any modification of osteoclast-mediated bone resorption by disease or drug treatment, however, elicits ...a parallel change in osteoblast-mediated bone formation because the processes are tightly coupled. Anabolic approaches now focus on uncoupling osteoblast action from osteoclast formation, for example, by inhibiting sclerostin, an inhibitor of bone formation that does not influence osteoclast differentiation. Here, we report that oncostatin M (OSM) is produced by osteoblasts and osteocytes in mouse bone and that it has distinct effects when acting through 2 different receptors, OSM receptor (OSMR) and leukemia inhibitory factor receptor (LIFR). Specifically, mouse OSM (mOSM) inhibited sclerostin production in a stromal cell line and in primary murine osteoblast cultures by acting through LIFR. In contrast, when acting through OSMR, mOSM stimulated RANKL production and osteoclast formation. A key role for OSMR in bone turnover was confirmed by the osteopetrotic phenotype of mice lacking OSMR. Furthermore, in contrast to the accepted model, in which mOSM acts only through OSMR, mOSM inhibited sclerostin expression in Osmr-/- osteoblasts and enhanced bone formation in vivo. These data reveal what we believe to be a novel pathway by which bone formation can be stimulated independently of bone resorption and provide new insights into OSMR and LIFR signaling that are relevant to other medical conditions, including cardiovascular and neurodegenerative diseases and cancer.
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