Citations

ABSTRACT Children and adolescents who sustain a distal forearm fracture (DFF) owing to mild, but not moderate, trauma have reduced bone strength and cortical thinning at the distal radius and tibia. Whether these skeletal deficits track into adulthood is unknown. Therefore, we studied 75 women and 75 men (age range, 20 to 40 years) with a childhood (age <18 years) DFF and 150 sex-matched controls with no history of fracture using high-resolution peripheral quantitative computed tomography (HRpQCT) to examine bone strength (ie, failure load) by micro–finite element (µFE) analysis, as well as cortical and trabecular bone parameters at the distal radius and tibia. Level of trauma (mild versus moderate) was assigned using a validated classification scheme, blind to imaging results. When compared to sex-matched, nonfracture controls, women and men with a mild trauma childhood DFF (eg, fall from standing height) had significant reductions in failure load (p < 0.05) of the distal radius, whereas women and men with a moderate trauma childhood DFF (eg, fall while riding a bicycle) had values similar to controls. Consistent findings were observed at the distal tibia. Furthermore, women and men with a mild trauma childhood DFF had significant deficits in distal radius cortical area (p < 0.05), and significantly lower dual-energy X-ray absorptiometry (DXA)-derived bone density at the radius, hip, and total body regions compared to controls (all p < 0.05). By contrast, women and men with a moderate trauma childhood DFF had bone density, structure, and strength that did not differ significantly from controls. These findings in young adults are consistent with our observations in children/adolescents with DFF, and they suggest that a mild trauma childhood DFF may presage suboptimal peak bone density, structure, and strength in young adulthood. Children and adolescents who suffer mild trauma DFFs may need to be targeted for lifestyle interventions to help achieve improved skeletal health. © 2014 American Society for Bone and Mineral Research.

Background The utility of longitudinal, circumferential, and radial strain and strain rate in determining prognosis in chronic heart failure is not well established. Methods and Results In 416 patients with chronic systolic heart failure, we performed speckle‐tracking analyses of left ventricular longitudinal, circumferential, and radial strain and strain rate on archived echocardiography images (30 frames per second). Cox regression models were used to determine the associations between strain and strain rate and risk of all‐cause mortality, cardiac transplantation, and ventricular‐assist device placement. The area under the time‐dependent ROC curve ( AUC ) was also calculated at 1 year and 5 years. Over a maximum follow‐up of 8.9 years, there were 138 events (33.2%). In unadjusted models, all strain and strain rate parameters were associated with adverse outcomes ( P <0.001). In multivariable models, all parameters with the exception of radial strain rate ( P =0.11) remained independently associated, with patients in the lowest tertile of strain or strain rate parameter having a ≈2‐fold increased risk of adverse outcomes compared with the reference group ( P <0.05). Addition of strain to ejection fraction ( EF ) led to a significantly improved AUC at 1 year (0.697 versus 0.633, P =0.032) and 5 years (0.700 versus 0.638, P =0.001). In contrast, strain rate did not provide incremental prognostic value to EF alone. Conclusions Longitudinal and circumferential strain and strain rate, and radial strain are associated with chronic heart failure prognosis. Strain provides incremental value to EF in the prediction of adverse outcomes, and with additional study may be a clinically relevant prognostic tool.

SummaryMultiple myeloma, the second most common haematological malignancy in the U.S., is currently incurable. Disruption of the intrinsic apoptotic pathway by BCL2 and MCL1 upregulation is observed in >80% of myeloma cases and is associated with an aggressive clinical course. Remarkably, there is no approved drug with the ability to target BCL2 or MCL1. Thus, we investigated the anti‐tumour effects of a pan‐BCL2 inhibitor, AT‐101, which has high binding specificity for BCL2 and MCL1 in preclinical models of plasma cell cancers (Multiple myeloma and Waldenström macroglobulinaemia). Gene expression and immunoblot analysis of six plasma cell cancer models showed upregulation of BCL2 family members. AT‐101 was able to downregulate BCL2 and MCL1 in all plasma cell cancer models and induced apoptotic cell death in a caspase‐dependent manner by altering mitochondrial membrane permeability. This cytotoxic effect and BCL2 downregulation were further potentiated when AT‐101 was combined with lenalidomide/dexamethasone (LDA). NanoString nCounter mRNA quantification and Ingenuity Pathways Analysis revealed differential changes in the CCNA2, FRZB, FYN, IRF1, PTPN11 genes in LDA‐treated cells. In summary, we describe for the first time the cellular and molecular events associated with the use of AT‐101 in combination with lenalidomide/dexamethasone in preclinical models of plasma cell malignancy.

Abstract Smoldering multiple myeloma (SMM) bridges the gap between monoclonal gammopathy of undetermined significance (a mostly premalignant disorder) and active multiple myeloma (MM). Until recently, no interventional study in patients with SMM showed improved overall survival (OS) with therapy as compared with observation. A report from the PETHEMA-GEM (Programa Español de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among patients with high-risk SMM who were treated with lenalidomide and dexamethasone. This unique study prompted us to review current knowledge about SMM and address the following questions: (1) Are there patients currently defined as SMM who should be treated routinely? (2) Should the definitions of SMM and MM be reconsidered? (3) Has the time come when not treating is more dangerous than treating? (4) Could unintended medical harm result from overzealous intervention? Our conclusion is that those patients with the highest-risk SMM (extreme bone marrow plasmacytosis, extremely abnormal serum immunoglobulin free light chain ratio, and multiple bone lesions detected only by modern imaging) should be reclassified as active MM so that they can receive MM-appropriate therapy and the paradigm of careful observation for patients with SMM can be preserved.

The acromelic dysplasias comprise short stature, hands and feet, and stiff joints. Three disorders are ascribed to this group, namely Weill–Marchesani syndrome, geleophysic dysplasia, and acromicric dysplasia, although similar in phenotype, can be distinguished clinically. Weill–Marchesani syndrome, on the basis of microspherophakia and ectopia lentis; geleophysic dysplasia by progressive cardiac valvular thickening, tracheal stenosis, and/or bronchopulmonary insufficiency, often leading to early death. Microspherophakia has not been reported previously in geleophysic dysplasia. Mutations in FBN1, ADAMTS10, or ADAMTS17 cause Weill–Marchesani syndrome by disrupting the microfibrillar environment, while geleophysic dysplasia is associated with enhanced TGF‐β signaling mediated through mutations in FBN1 or ADAMTSL2. We studied a 35‐year‐old woman with geleophysic dysplasia, with short stature, small hands and feet, limitation of joint mobility, mild skin thickening, cardiac valvular disease, restrictive pulmonary disease, and microspherophakia. Sequencing of ADAMTSL2 demonstrated two changes: IVS8‐2A>G consistent with a disease‐causing mutation, and IVS14‐7G>A with potential to generate a new splice acceptor site and result in aberrant mRNA processing. The unaffected mother carries only the IVS8‐2A>G transition providing evidence that the two changes are in trans‐configuration in our patient. © 2013 Wiley Periodicals, Inc.